ES2946001T3 - Pyrazole amide compounds as IRAK inhibitors - Google Patents

Abstract

The described embodiments relate to new interleukin receptor associated kinase (IRAK) inhibitors of formula 1 and compositions comprising said inhibitors. Methods for preparing and using the compounds and compositions are also described. The disclosed compounds and/or compositions may be used to treat or prevent a disease or condition associated with IRAQ. (Automatic translation with Google Translate, without legal value)

Description

DESCRIPTION

Pyrazole amide compounds as IRAK inhibitors

FIELD

This disclosure relates to amide compounds, and to embodiments of a method of making and using the compounds, such as for inhibiting interleukin receptor-associated kinase (IRAK), and for treating IRAK-related diseases and conditions.

BACKGROUND

Interleukin-1 receptor-associated kinases (IRAKs) are important mediators of signaling processes, such as toll-like receptors (TLRs) and interleukin-1 receptor (IL-1) signaling processes. 1R). IRAKs have been implicated in the modulation of signaling networks that control inflammation, apoptosis, and cell differentiation. Four IRAK genes have been identified in the human genome (IRAK1, IRAK ₂ , IRAK3 and IRAK4), and studies have revealed distinct and non-redundant biological roles. IRAK1 and IRAK4 have been shown to exhibit kinase activity. WO2015/068856 describes IRAK inhibitors.

SUMMARY

The invention is as defined in the claims. Accordingly, the invention provides a compound having a formula 1

or a salt thereof, wherein:

ring A is heteroaryl;

R1 is H or C _1-6 alkyl;

R2 is H, aliphatic, heteroaliphatic, or heterocyclyl;

each Z1, Z2, Z3, and Z4, is independently N or CR3, wherein at least one of Z1, Z2, Z3, and Z4 is N; each R3 is independently H, aliphatic, or heteroaliphatic; and

R4 is halogen, heteroaryl, heterocycloaliphatic, aryl, -NH-heteroaryl, or -O-heteroaryl.

The invention also provides a composition comprising a compound as defined above, and a pharmaceutically acceptable excipient.

Certain described embodiments refer to compounds having a formula 1

and/or a salt thereof. One skilled in the art will appreciate that compounds within formula 1 may also be solvates, including hydrates, N-oxides thereof. Referring to formula 1, ring A is heteroaryl, such as pyridinyl, or pyrazinyl. In particular embodiments, ring A is pyridin-2-yl. In other examples, ring A is

wherein each Q is independently CH, CRm, or N, Rm is Rb, and x is 0, 1, or 2; at least one Q is N. Rb is ^{independently at each occurrence -OH, -CF3 , -CN,} -O ^rc , ^{-SO2 Rc, -NRdRd, -N(H)SO2 Rc, -C(O)OH, -N (H)C(O)Rc,} -C(O)ORc, -C(O)NRdRd, =O, or halogen. Rc is independently, for each occurrence, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heteroalicyclyl, aralkyl, C _1-6 alkyl substituted with 1,2 or 3 Re, C ₅ aromatic _-10 , C _5-10 aromatic substituted with 1,2 or 3 Re. Rd is independently, for each occurrence, H, C _1-6 alkyl optionally substituted with 1,2 or 3 Re, C _3-6 cycloalkyl optionally substituted with 1, 2 or 3 Re, C _3-6 heteroalicyclyl optionally substituted with 1,2 or 3 Re, C _5-10 aromatic optionally substituted with 1,2 or 3 Ra or Rb, or two Rd groups, together with nitrogen attached thereto, form a C _3-6 heteroalicyclyl moiety optionally substituted with C _1-6 alkyl and optionally interrupted with one or two -O- or -N(R ₈ ), where R ₉ is R ₇ 0. Ra is independently, for each occurrence, H, D, C _1-6 alkyl, C _3-6 cycloalkyl, C _5-10 aromatic, or C _3-6 heterocycloaliphatic. Y Re is independently, for each occurrence, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, or -ORa.

R1 is H or C _1-6 alkyl; R2 is H, aliphatic, heteroaliphatic, or heterocyclyl, and can be H, 3-10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy and/or hydroxy substituted cyclohexyl, alkyl unsubstituted C _1-6 alkyl, or C _1-6 alkyl substituted with -OH, amino, alkoxy, or heterocycloaliphatic. In some embodiments, R2 is Ra, Ra substituted with Rb, Ra substituted with 1 or 2 Rc, or Ra substituted with Rd. And in particular embodiments, R2 is H, CH ₃ ,

In certain embodiments of Formula 1, Ring A is pyridinyl or pyrazinyl; R1 is H; and/or R2 is H, 3 to 10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy and/or hydroxy substituted cyclohexyl, unsubstituted C _1-6 alkyl, or C _1-6 substituted with -OH, amino, alkoxy, or heterocycloaliphatic.

Also with respect to formula 1, each Z1, Z2, Z3, and Z4 is independently N or CR3, wherein at least one of Z1, Z2, Z3, and Z4 is N, and each R3 is independently H, aliphatic, or heteroaliphatic. R4 can be halogen, heteroaryl, heterocycloaliphatic, aryl, -NH-heteroaryl, or -O-heteroaryl.

In some embodiments, the rest

is pyridinyl, pyrimidinyl, or pyrazinyl. In some examples, Z1 is N. In other examples, Z1 is N, and Z2, Z3, and Z4 are CR3; Z1 and Z2 are N, and Z3 and Z4 are CR3; Z1 and Z3 are N, and Z2 and Z4 are CR3; Z1 and Z4 are N, and Z2 and Z3 are CR3; or Z3 is N, and Z1, Z2, and Z4 are CR3. In any of the embodiments, R1 can be H.

R4 can be halogen, heterocycloaliphatic, aryl, heteroaryl, -NH-heteroaryl, or -O-heteroaryl, such as Br, 5-10 membered heteroaryl, 3-6 membered heterocycloaliphatic, 6-10 membered aryl, -NH- (5 to 10 membered heteroaryl), or -O-(5 to 10 membered heteroaryl). In some embodiments, R4 is pyridinyl, pyrimidinyl, pyrazolyl, NH-pyrazolyl, pyrrolyl, -O-pyridinyl -NH-pyridinyl, indolyl, furanyl, -NH-benzopyrazolyl, pyrrolopyridinyl, phenyl, tetrahydropyridinyl, piperidinyl, or 2-oxo-1,2-dihydropyridinyl. In other examples, R4 is Br,

wherein y is 0, 1, or 2, and each Rp is independently Ra, Rb, Ra substituted with Rb, oo R Ra substituted Rp can independently be -CH ³ , -OCH ³ , -NH ² , -CF ³ , F , -CN,

In particular embodiments, R4 is Br; unsubstituted pyridinyl; C _1-6 alkyl-substituted pyridinyl, haloalkyl, amino, heterocycloaliphatic, cycloalkyl, -CN, alkoxy, -O-heterocycloaliphatic, -NH-heterocycloaliphatic, halogen, sulfonamide, -O-benzyl, carboxyl, sulfonyl, -NH-cycloalkyl , or amide; unsubstituted pyrimidinyl; unsubstituted pyrazolyl; pyrazolyl substituted with C _1-6 alkyl; -NH-pyrazolyl unsubstituted; -NH-pyrazolyl substituted with C _1-6 alkyl, or heteroaryl; pyrrolyl; -O-pyridinyl unsubstituted; -O-pyridinyl substituted with amino; -NH-pyridinyl substituted with C _1-6 alkyl, haloalkyl, or heterocycloaliphatic; unsubstituted indolyl; alkoxy substituted indolyl; furanyl; -NH-benzopyrazolyl; pyrrolopyridinyl; unsubstituted phenyl; phenyl substituted with halogen, C _1-6 alkyl, alkoxy, -CN, amino, or sulfonamide; unsubstituted tetrahydropyridinyl; tetrahydropyridinyl substituted with tert-butoxycarbonyl; piperidinyl; or 2-oxo-1,2-dihydropyridinyl.

The described compounds can also have a formula 2

and/or a salt, solvate, N-oxide, thereof, wherein the common substituents are as set forth for Formula 1, and R5, R6, and _R7 are each independently H or alkyl, such as C _1-6 alkyl. In some examples, R5, R6, and R' are each H. In some embodiments of formula 2, ring A is pyridin-2-yl, or pyrazin-2-yl.

Also described are compounds having the formula 3

and/or a salt, solvate, N-oxide, thereof, wherein the common substituents are as set forth for formulas 1 and 2, and _R8 , R9, R10, and R11 are each independently H, aliphatic , halogen, heterocycloaliphatic, alkoxy, or -O-heterocycloaliphatic, such as H, halogen, 3- to 6-membered heterocycloaliphatic, alkoxy, or -O-(3- to 6-membered heterocycloaliphatic). In certain embodiments, R ₈ is H or halogen; R9 and R11 are H; and/or R10 is H, F, morpholino, N-methylpiperidin-1-yl, methoxy, 2-hydroxy-2-methylpropoxy, or -O-oxetanyl. And in particular embodiments, each of R ₈ , R 9 , and R 11 is H; R9 and R11 are H, and _R8 and R10 are F; or _R8 , R9, R10, and R11 are each H.

The described compounds can also have a formula 8

and/or a salt, solvate, N-oxide, thereof, in which the substituents are as set forth for Formulas 1-3. In some embodiments, R1 is H; R2 is H, 3 to 10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy and/or hydroxy substituted cyclohexyl, unsubstituted C _1-6 alkyl, or C alkyl _1-6 substituted with -OH, amino, alkoxy, or heterocycloaliphatic; R4 is Br; unsubstituted pyridinyl; C _1-6 alkyl-substituted pyridinyl, haloalkyl, amino, heterocycloaliphatic, cycloalkyl, -CN, alkoxy, -O-heterocycloaliphatic, -NH-heterocycloaliphatic, halogen, sulfonamide, -O-benzyl, carboxyl, sulfonyl, -NH-cycloalkyl , or amide; unsubstituted pyrimidinyl; unsubstituted pyrazolyl; pyrazolyl substituted with C _1-6 alkyl; -NH-pyrazolyl unsubstituted; -NH-pyrazolyl substituted with C _1-6 alkyl, or heteroaryl; pyrrolyl; -O-pyridinyl unsubstituted; -O-pyridinyl substituted with amino; -NH-pyridinyl substituted with C _1-6 alkyl, haloalkyl, or heterocycloaliphatic; unsubstituted indolyl; alkoxy substituted indolyl; furanyl; -NH-benzopyrazolyl; pyrrolopyridinyl; unsubstituted phenyl; phenyl substituted with halogen, C _1-6 alkyl, alkoxy, -CN, amino, or sulfonamide; unsubstituted tetrahydropyridinyl; tetrahydropyridinyl substituted with tert-butoxycarbonyl; piperidinyl; or 2-oxo-1,2-dihydropyridinyl; R ₈ is H or F; R9 and R11 are H; and R10 is H, F, morpholino, N-methylpiperidinyl, methoxy, 2-hydroxy-2-methylpropoxy, or -O-oxetanyl. And in particular embodiments, each of R ₈ , R 9 , R 10 and R 11 is H; R ₈ , R 9 , and R 11 is H and R 10 is 3- to 6-membered morpholino or N-methylpiperidinyl, methoxy, 2-hydroxy-2-methylpropoxy, or -O-oxetanyl; or R ₈ and R10 are F, and R9 and R11 are H.

Compounds according to the present disclosure may also be formulated as compositions comprising one or more compounds according to any of formulas 1-9 and a pharmaceutically acceptable excipient. Compositions of this type can also include an additional therapeutic agent.

Methods of making and using said compounds and compositions are also described (it should be noted, for the avoidance of doubt, that any references disclosed to methods of medical treatment using the compounds and compositions are not part of the invention, but rather in the context of the invention should be rather be construed as the compounds and compositions for use in the relevant methods of medical treatment). For example, a described method of using compounds within formulas 1-9 comprises administering to a subject in need thereof an effective amount of one compound, two or more compounds, or a composition comprising at least one compound, according to any or all formulas 1-9. The method may be particularly suitable for treating a disease or condition for which an IRAK inhibitor is indicated, including an IRAK1 inhibitor, IRAK ₂ , IRAK3 and/or IRAK4. The disease may be autoimmune disease, inflammatory disorder, cardiovascular disease, neurodegenerative disorder, allergic disorder, multi-organ failure, kidney disease, platelet aggregation disease, cancer, transplantation, sperm motility, erythrocyte deficiency , graft rejection, lung injury, respiratory disease, ischemic condition, bacterial infection, viral infection, immune regulation disorder, or a combination thereof.

The described methods for using compounds according to formulas 1-9 also include inhibiting an IRAK protein by contacting the IRAK protein with an effective amount of a compound or compounds, or a composition comprising a compound or compounds, according to either or all of formulas 1-9, where the compound has an EC ⁵⁰ greater than 0 to 5 µM, typically 0 to 1 µM, and with many compounds disclosed having an EC ⁵⁰ substantially less than 1 µM. The IRAK protein may be in a subject, or the method may ^{comprise contacting the IRAK protein} in vitro.

The foregoing and other objects, features, and advantages of the invention will become more apparent from the following detailed description.

DETAILED DESCRIPTION

I. Definitions

The following explanations of terms, expressions, and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. The singular forms "un", "una" and "el", "la" refer to one or more than one, unless the context clearly indicates otherwise. The term "or" refers to a single item of set alternative items or a combination of two or more items, unless the context clearly indicates otherwise. As used herein, "comprises" means "includes". Therefore, "comprising A or B" means "including A, B or A and B", without excluding additional elements.

Unless otherwise indicated, all numbers expressing amounts of components, molecular weights, percentages, temperatures, times, etc., as used in the specification or claims, are to be understood as modified by the term "about". Therefore, unless explicitly or implicitly stated otherwise, the reported numerical parameters are approximations that may depend on the desired properties being sought and/or detection limits under standard conditions/test methods. When directly and explicitly distinguishing the discussed prior art embodiments, the embodiment numbers are not approximate, unless the word "approximately" is expressly mentioned.

Unless otherwise explained, all technical and scientific expressions and terms used in this specification have the same meaning as is commonly understood by an ordinary person skilled in the art to which this disclosure pertains. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting.

When depicting or describing chemical structures, unless explicitly stated otherwise, all carbons are assumed to include hydrogen, so each carbon fits a valence of four. For example, in the structure on the left side of the following diagram there are nine hydrogen atoms involved. The nine hydrogen atoms are represented in the structure on the right.

Sometimes a particular atom in a structure is described in a textual formula as having hydrogen or hydrogen atoms, for example -CH ² CH ² -. A person of ordinary skill in the art will understand that the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity in the description of organic structures.

If a group R is represented as "floating" in a ring system such as, for example, in the group:

then, unless otherwise defined, a substituent R may reside on any atom in the fused bicyclic ring system, excluding the atom bearing the bond with the symbol "

J V U V

", provided a stable structure is formed. In the depicted example, the R group may reside on either a 5-membered or 6-membered ring atom of the indolyl ring system.

When there is more than one of these "floating" groups represented such as, for example, in the formulas:

in that there are two groups, namely the R and the bond indicating attachment to a parent structure; then, unless otherwise defined, "floating" groups may reside on any atom in the ring system, again assuming that each replaces a depicted, implicitly, or expressly defined hydrogen in the ring system and that an arrangement of this type would form a chemically stable compound.

When a group R is represented as existing in a ring system such as, for example, in the formula:

where, in this example, y can be more than one, assuming each replaces a currently represented, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, two Rs may reside on the same carbon. A simple example is when R is a methyl group. The depicted structure can exist as a geminal dimethyl on a depicted ring carbon (a "ring" carbon). In another example, two Rs on the same carbon, including that same carbon, can form a ring, thus creating a spirocyclic ring structure (a "spirocyclyl" group). For example, as shown below, two Rs can form a piperidine ring in a spirocyclic arrangement with cyclohexane, such as

As used herein, the term "substituted" refers to all subsequent modifiers in a term; for example, in the term "substituted C ^1-8 arylalkyl", substitution can occur on the "C ^1-8 alkyl portion", the "aryl" portion, or on both portions of the C ^1-8 arylalkyl group .

"Substituted", when used to modify a specified group or moiety, means that at least one, and perhaps two or more, hydrogen atoms of the specified group or moiety are independently replaced with the same or different substituent groups as defined below. In a particular embodiment, a group, moiety, or substituent may be substituted or unsubstituted, unless expressly defined as "unsubstituted" or "substituted." Accordingly, any of the groups specified herein may be substituted or unsubstituted. In particular embodiments, the substituent may or may not be expressly defined as substituted, but is still contemplated to be optionally substituted. For example, an "alkyl" or "pyrazolyl" moiety may be unsubstituted or substituted, but an "unsubstituted alkyl" or "unsubstituted pyrazolyl" is unsubstituted.

"Substituents" or "substituent groups" for substituting one or more hydrogen atoms on saturated carbon atoms in the specified group or moiety are, unless otherwise specified, -R60, halo, =O, -OR70, - SR70, -N(R80) ² , haloalkyl, perhaloalkyl, -CN, -NOz, =N ² , -N ³ , -SO ₂ R ⁷⁰ , -SO ₃ -M+, -SO ³ R ⁷⁰ , -OSO ₂ R ⁷⁰ , -OSO ₃ -M+ -OSO ³ R ⁷⁰ , -P(O)(O-) ² (M+) ² , -P(O)(O-) ² M2+, -P(O)(OR70)O-M+ , -P(O)(OR70) ² , -C(O)R70, -C(S)R70, -C(NR70)R70, -CO ² -M+, -CO ² R ⁷⁰ , -C(S)OR70 , -C(O)N(R80) ² , -C(NR70)(R80) ² , -OC(O)R70, -OC(S)R70, -OCO ² -M+, -OCO ² R ⁷⁰ , -OC (S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO ² -M+, -NR70CO ² R ₇ 0, -NR70C(S)OR70, -NR70C(O)N(R80) ² , -NR70C(NR70)R70 and -NR70C(NR70)N(R80) ² , where R60 is C ^1-10 aliphatic, heteroaliphatic or cycloaliphatic, typically C _1-6 aliphatic, more typically C _1- alkyl ₆ , where R60 may optionally be substituted; each R ₇ 0 is independently, for each occurrence, hydrogen or R60; each R ₈ 0 is independently, for each occurrence, R ₇ 0, or alternatively, two R ₈ 0 groups, taken together with the nitrogen atom to which they are attached, form a 3 to 7-membered heterocycloaliphatic, optionally including 1 to 4 of the same or different additional heteroatoms selected from O, N and S, of which N optionally has R ₇ 0 substitution, such as H or C ¹ -C ³ alkyl substitution; and each M+ is a counterion with a single net positive charge. Each of the M+ is independently for each occurrence, for example, an alkali metal ion, such as K+, Na+, Li+; an ammonium ion, such as N(R60)4; an amino acid ion protonated, such as a lysine ion or an arginine ion; or an alkaline earth metal ion, such as [Ca2+] ^0.5 , [Mg2+] ^0.5 or [Ba2+]0.5 (a subscript "0.5" means, for example, that one of the counterions for divalent alkaline earth ions may be an ionized form of one compound of the invention and the other a typical counterion such as chloride, or two ionized compounds can serve as counterions for divalent alkaline earth ions of this type, or one doubly ionized compound can serve as the counterion for divalent alkaline earth ions of this type) . As specific examples, -N(R80) ² includes -NH ² , -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl, N-morpholinyl , and the like. Any two hydrogen atoms on a single carbon may also be replaced, for example, with =O, =NR70, =N-OR70, =N ² or =S.

Substituent groups for replacing hydrogen atoms on unsaturated carbon atoms in groups containing unsaturated carbons are, unless otherwise specified, -R60, halo, -O-M+, -OR70, -SR70, -S-M+,

-N(R80) ² , haloalkyl, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NOz, -N ³ , -SO ₂ R ⁷⁰ , -SO ₃ -M+, -SO ³ R ⁷⁰ , -OSO ₂ R70,

-OSO ³ -M+ -OSO ³ R ⁷⁰ , -PO ₃ -2(M+) ₂ , -PO ³ -2M2+, -P(O)(OR70)O-M+, -P(O)(OR70) ² , - C(O)R70,

-C(S)R70, -C(NR70)R70, -CO ₂ -M+, -CO ₂ R70, -C(S)OR70, -C(O)NR80R80, -C(NR70)N(R80) ₂ ,

-OC(O)R70, -OC(S)R70, -OCO ₂ -M+, -OCO ₂ R70, -OC(S)OR70, -NR70C(O)R70,

-NR70C(S)R70, -NR70CO ₂ -M+, -NR70CO ₂ R70, -NR70C(S)OR70, -NR70C(O)N(R80) ₂ ,

-NR70C(NR70)R70 and -NR70C(NR70)N(R80) ² , where R60, R ₇ 0, R ₈ 0 and M+ are as defined above, provided that, in the case of alkene or substituted alkyne, the substituents are not -O-M+, -OR70, -SR70, or -S-M+.

Substituent groups for replacing hydrogen atoms on nitrogen atoms in groups containing such nitrogen atoms are, unless otherwise specified, -R60, -O-M+, -OR70, -SR70, -S-M+, - N(R80) ² , haloalkyl, perhaloalkyl, -CN, -NO, -NOz,

-S(O) ² R ₇ 0, -SO ₃ -M+, -SO ³ R ⁷⁰ , -OS(O) ² R ₇ 0, -OSO ₃ -M+ -OSO ³ R ⁷⁰ , -PO ₃ 2-(M+ ) ₂ ,

-PO ₃ 2-M2+, -P(O)(OR70)O-M+, -P(O)(OR70)(OR70), -C(O)R70, -C(S)R70, -C(NR70) R70,

-CO ₂ R70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OCO ₂ R70,

-OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO ₂ R70, -NR70C(S)OR70, -NR70C(O)N(R80) ₂ ,

-NR70C(NR70)R70 and -NR70C(NR70)N(R80) ² , where R60, R ₇ 0, R ₈ 0 and M+ are as defined above.

In one embodiment, a group that is substituted has at least one substituent up to the number of substituents possible for a particular moiety, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents.

Additionally, in embodiments where a group or moiety is substituted with a substituted substituent, the nesting of such substituted substituents is limited to three, thus avoiding polymer formation. Therefore, in a group or moiety that comprises a first group that is a substituent in a second group that is in turn a substituent in a third group, which is attached to the original structure, the first (outermost) group only it may be substituted with unsubstituted substituents. For example, in a group comprising -(aryl-1)-(aryl-2)-(aryl-3), the aryl-3 can only be substituted with substituents that are unsubstituted.

Any group or moiety defined herein can be connected to any other part of a disclosed structure, such as a parent or core structure, as would be understood by one of ordinary skill in the art, for example, when considering valence rules, comparison with exemplary species and/or considering functionality, unless the connectivity of the group or moiety with the other part of the structure is expressly stated or implied by the context.

"Acyl" refers to the group -C(O)R, where R is H, aliphatic, heteroaliphatic, heterocyclic, or aromatic. Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O) ^C1 - ^C6alkyl , -C(O)C1 ^- C6haloalkyl , -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl or -C(O)heterocyclyl. Specific examples include -C(O)H, -C(O)Me, -C(O)Et or -C(O)cyclopropyl.

"Aliphatic" refers to a substantially hydrocarbon-based group or moiety. An aliphatic group or moiety can be acyclic, including alkyl, alkenyl or alkynyl groups, cyclic versions thereof, such as cycloaliphatic groups or moieties including cycloalkyl, cycloalkenyl or cycloalkynyl, and further including straight and branched chain arrangements, and likewise all stereoisomers and positional isomers. Unless stated expressly to the contrary, an aliphatic group contains from one to twenty-five carbon atoms (C ^1-25 ); for example, from one to fifteen (C ^1-15 ), from one to ten (C ^1-10 ), from one to six (C _1-6 ), or from one to four carbon atoms (C ^1-4 ) for an acyclic aliphatic group or residue, or from three to fifteen (C ^3-15 ), from three to ten (C ^3-10 ), from three to six (C _3-6 ), or from three to four (C ^{3- 4} ) carbon atoms for a cycloaliphatic group or moiety. An aliphatic group may be substituted or unsubstituted, unless expressly referred to as an "unsubstituted aliphatic" or a "substituted aliphatic". An aliphatic group may be substituted with one or more substituents (up to two substituents for each methylene carbon in an aliphatic chain, or up to one substituent for each carbon of a -C=C- double bond in an aliphatic chain, or up to one substituent for a carbon of a terminal methine group).

"Lower aliphatic" refers to an aliphatic group containing one to ten carbon atoms (C ^1-10 ), such as one to six (C _1-6 ), or one to four (C ^1-4 ). carbon atoms; or three to ten (C ^3-10 ), such as three to six (C _3-6 ) carbon atoms for a lower cycloaliphatic group.

"Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl group. In certain examples, R is a C _1-6 alkyl group or a C _3-6 cycloalkyl group. Methoxy (-OCH ³ ) and ethoxy (-OCH ² CH ³ ) are exemplary alkoxy groups. In a substituted alkoxy, R is substituted alkyl or substituted cycloalkyl, examples of which in the compounds described herein include haloalkoxy groups, such as -OCF ² H.

"Alkoxyalkyl" refers to the group -alkyl-OR, where R is a substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl group.

"Alkyl" refers to a saturated aliphatic hydrocarbyl group having 1 to 25 (C ^1-25 ) carbon atoms, typically 1 to 10 (C ^1-10 ) carbon atoms, such as 1 to 6 (C _{1 -6} ) carbon atoms. An alkyl moiety can be substituted or unsubstituted. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH ³ ), ethyl (-CH ² CH ³ ), n-propyl (-CH ² CH ² CH ³ ), isopropyl (-C ^h ( CH ₃ ) ₂ ), n-butyl (-CH ² -CH ² CH ² CH ³ ), isobutyl (-CH ² CH ² (CH ³ ) ² ), sec-butyl (-CH(CH ³ )(CH ² CH ³ ), t-butyl (-C(CH ³ ) ³ ), n-pentyl (-CH ² CH ² CH ² CH ² CH ³ ), and neopentyl (-CH ₂ C(CH ₃ ) ₃ ).

"Amino" refers to the group -NH ² , -NHR or -NRR, where each R is independently selected from H, aliphatic, heteroaliphatic, aromatic, including both aryl and heteroaryl, or heterocycloaliphatic, or two R groups, together with the nitrogen attached to them form a heterocyclic ring. Examples of such heterocyclic rings include those in which two R groups, together with the nitrogen to which they are attached, form a -(CH ₂ ) ₂ -5- ring, optionally interrupted by one or two heteroatom groups, such as - O- or -N(R ₈ ) as in the groups

where Rg is R ₇ 0, -C(O)R70, -C(O)OR60, or -C(O)N(R8V

"Amide" or "carboxamide" refers to the group -N(R)acyl, or -C(O)amino, where R is hydrogen, heteroaliphatic or aliphatic, such as alkyl, particularly C _1-6 alkyl.

"Romantic A" refers to a conjugated cyclic group or moiety of, unless otherwise specified, 5 to 15 ring atoms, having a single ring (for example, phenyl, pyridinyl, or pyrazolyl) or multiple fused rings in those in which at least one ring is aromatic (eg, naphthyl, indolyl, or pyrazolopyridinyl), ie, at least one ring, and optionally multiple fused rings, have a continuous n delocalized electron system. Typically, the number of out-of-plane electrons n corresponds to Hückel's rule (4n 2). The point of attachment to the backbone is typically via an aromatic portion of the fused ring system. For example,

However, in certain examples, the context or the express disclosure may indicate that the point of attachment is through a non-aromatic portion of the fused ring system. For example,

. An aromatic group or moiety may comprise only ring carbon atoms such as in an aryl group or moiety, or may comprise one or more ring carbon atoms and one or more ring heteroatoms comprising a single pair of electrons (eg, S, O, N, P, or Si) such as in a heteroaryl group or moiety. Unless otherwise indicated, an aromatic group may be substituted or unsubstituted.

"Aryl" refers to an aromatic carbocyclic group of, unless otherwise specified, 6 to 15 carbon atoms, having a single ring (for example, phenyl) or multiple fused rings, in which at least one ring is aromatic (for example, 1,2,3,4-tetrahydroquinoline, benzodioxole, and the like). If any part of the aromatic ring contains a heteroatom, the group is heteroaryl and not aryl. Aryl groups can be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise indicated, an aryl group may be substituted or unsubstituted.

"Liphatic A ra" refers to an aryl group attached to the parent through an aliphatic moiety. Araliphatic includes aralkyl or arylalkyl groups such as benzyl and phenylethyl.

"Carboxyl" or "carboxyl tho" refers to -COzH, -C(O)O-, or salts thereof.

"Carboxylic ester" or "carboxy ester" refers to the group -C(O)OR, where R is aliphatic, heteroaliphatic, cyclic, heterocyclic, and aromatic, including both aryl and heteroaryl.

°C iano" refers to the group -CN.

°C "cycloaliphatic" refers to a cyclic aliphatic group having a single ring (eg, cyclohexyl), or multiple rings, such as in a fused, bridged, or spirocyclic system, at least one of which is aliphatic. Typically, the point of attachment to the backbone is through an aliphatic portion of the multiple ring system.Cycloaliphatic includes saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl.A cycloaliphatic group can contain from three to twenty-five carbon atoms; for example , three to fifteen, three to ten, or three to six carbon atoms. Unless otherwise indicated, a cycloaliphatic group may be substituted or unsubstituted. Exemplary cycloaliphatic groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl or cyclohexenyl.

"Halo," "halide" or "halogen" refers to fluoro, chloro, bromo, or iodo.

"Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CH ² F, -CHF ² and -CF ³ .

"Heteroaliphatic" refers to an aliphatic compound or group having at least one heteroatom and at least one carbon atom, that is, one or more carbon atoms of an aliphatic compound or group comprising at least two carbon atoms have been replaced by an atom that has at least one lone pair of electrons, usually nitrogen, oxygen, phosphorus, silicon, or sulfur. Heteroaliphatic compounds or groups may be substituted or unsubstituted, branched or unbranched, chiral or achiral, and/or acyclic or cyclic such as a heterocycloaliphatic group.

"Heteroaryl" refers to an aromatic group or moiety of, unless otherwise specified, 5 to 15 ring atoms, comprising at least one carbon atom and at least one heteroatom, such as N, S, O, P or if. A heteroaryl group or moiety can comprise a single ring (eg, pyridinyl, pyrimidinyl, or pyrazolyl) or multiple fused rings (eg, indolyl, benzopyrazolyl, or pyrazolopyridinyl). Heteroaryl groups or moieties can be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise indicated, a heteroaryl group or moiety may be substituted or unsubstituted.

"Heterocyclyl", "heterocycle" and "heterocycle" refer to both aromatic and non-aromatic ring systems, and more specifically refer to a three to fifteen membered stable ring moiety comprising at least one carbon atom, and typically several carbon atoms, and at least one, such as one to five, heteroatoms. The heteroatom(s) may be nitrogen, phosphorus, oxygen, silicon or sulfur atoms. The heterocyclyl moiety may be a monocyclic moiety or may comprise multiple rings such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. A multi-ring moiety can include fused or bridged ring systems, as well as spirocyclic systems; and any nitrogen, phosphorous, carbon, silicon, or sulfur atoms in the heterocyclyl moiety may optionally be oxidized to various oxidation states. For convenience, nitrogens, particularly, but not exclusively, those defined as ring aromatic nitrogens, include their corresponding N-oxide form, although they are not explicitly defined as such in a particular example. Thus, for a compound having, for example, a pyridinyl ring, the corresponding pyridinyl-N-oxide is included as another compound of the invention, unless expressly excluded or excluded by context. In addition, the ring nitrogen atoms may optionally be quaternized. Heterocycle includes heteroaryl moieties, and "heteroalicyclylic" or "heterocycloaliphatic" moieties, which are heterocyclyl rings that are partially or fully saturated. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purin yl, quinazolinyl, quinoxalinyl , quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidinyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazole yl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl.

"Hydroxy" refers to the group -OH.

"Nitro" refers to the group -NOz.

"Phosphate" refers to the group -OP(O)(OR') ² , where each -OR' is independently -OH; -O-aliphatic, such as -O-alkyl or -O-cycloalkyl; -O-aromatic, including both -O-aryl and -O-heteroaryl; -O-aralkyl; u -OR' is -O-M+, where each M+ is a positively charged counterion. By way of example, M+ can be an alkali metal ion, such as K+, Na+, Li+; an ammonium ion, such as N(R") ⁴ , where R" is H, aliphatic, heterocyclyl, or aryl; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba21]0.5. Phosphono-oxyalkyl refers to the group -alkyl-phosphate, such as, for example, -CH ² OP(O)(OH) ² , or a salt thereof, such as -CH ² OP(O)(O-Na+) ² , and (((dialkoxyphosphoryl)oxy)alkyl) refers to the dialkyl ester of a phosphono-oxyalkyl group such as, for example, -CH ² OP(O)(O-tert-butyl) ² .

"Phosphonate" refers to the group -P(O)(OR') ² , where each -OR' is independently -OH; -O-aliphatic, such as -O-alkyl or -O-cycloalkyl; -O-aromatic, including both -O-aryl and -O-heteroaryl; u -O-aralkyl; u -OR' is -O-M+, where each M+ is a positively charged counterion. By way of example, M+ can be an alkali metal ion, such as K+, Na+, Li+; an ammonium ion, such as N(R")4, where R" is H, aliphatic, heterocyclyl, or aryl; or an alkaline earth ion, such as [Ca21]0.5, [Mg2+]0.5, or [Ba21]0.5. "Phosphonoalkyl" refers to the group -alkyl-phosphonate, such as, for example, -CH ² P(O)(OH) ² , or CH ² P(O)(O-Na+) ² and (((dialkoxyphosphoryl)oxy)alkyl ) refers to the dialkyl ester of a phosphonoalkyl group such as, for example, -CH ² P(O)(O-tert.-butyl) ² .

"Patient" or "Subject" refers to mammals and other animals, particularly humans. Therefore, the described methods are applicable to both human therapy and veterinary applications.

"Pharmaceutically acceptable carrier" refers to a substance, other than the active ingredient, that is included in a formulation of the active ingredient. As used herein, an excipient can be incorporated into particles of a pharmaceutical composition, or it can be physically mixed with particles of a pharmaceutical composition. An excipient can be used, for example, to dilute an active agent and/or to modify properties of a pharmaceutical composition. Excipients may include, but are not limited to release agents, binders, coatings, enteric coatings, disintegrants, flavors, sweeteners, colorants, lubricants, glidants, absorbents, preservatives, adjuvants, carriers, or vehicles. The excipients can be starches and modified starches, cellulose and cellulose derivatives, saccharides and their derivatives, such as disaccharides, polysaccharides and sugar alcohols, proteins, synthetic polymers, cross-linked polymers, antioxidants, amino acids or preservatives. Exemplary excipients include, but are not limited to magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starches, hydroxypropyl cellulose, hydroxypropyl methylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopherol. polyethylene glycol 1000 succinate (also known as vitamin E TPGS or TPGS), carboxymethyl cellulose, dipalmitoyl phosphatidyl choline (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate , methylparaben, propylparaben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or lanolin.

An "adjuvant" is an excipient that modifies the effect of other agents, typically the active ingredient. Adjuvants are often pharmacological and/or immunological agents. An adjuvant can modify the effect of an active ingredient by increasing an immune response. An adjuvant can also act as a stabilizing agent for a formulation. Exemplary adjuvants include, but are not limited to aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and combined adjuvants such as Freund's complete adjuvant or Freund's incomplete adjuvant.

"Pharmaceutically acceptable carrier" refers to an excipient that is a carrier or vehicle, such as a suspending aid, solubilization aid, or aerosolization aid. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Publisher, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21st Edition (2005), describes exemplary compositions and formulations suitable for pharmaceutical administration of one or more additional pharmaceutical compositions and agents.

In general, the nature of the carrier will depend on the particular mode of administration that is employed. For example, parenteral formulations usually comprise injectable fluids including pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol, or the like as a vehicle. In some examples, the pharmaceutically acceptable carrier may be sterile to be suitable for administration to a subject (eg, by parenteral, intramuscular injection or subcutaneous). In addition to biologically neutral carriers, the pharmaceutical compositions to be administered may contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.

"Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound that are derived from a variety of organic and inorganic counterions as will be known to one of ordinary skill in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like; and when the molecule contains basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that retain the biological efficacy of free bases while being formed by acidic participants. In particular, the disclosed compounds form salts with a variety of pharmaceutically acceptable acids, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid, and the like. "Pharmaceutically acceptable basic addition salts" are a subset of "pharmaceutically acceptable salts" that are derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Exemplary salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine. , triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19.) In particular disclosed embodiments, the amide compounds can be formate, trifluoroactate, hydrochloride , or sodium salt.

"Effective amount", with respect to a compound or composition, refers to an amount of the compound or composition sufficient to achieve a particular desired result, such as inhibiting a protein or enzyme, particularly an IRAK kinase; to elicit a desired biological or medical response in a tissue, system, subject, or patient; to treat a specific disease or disorder; to ameliorate or eradicate one or more of your symptoms; and/or to prevent the onset of the disease or disorder. The amount of a compound constituting an "effective amount" may vary depending on the compound, the desired result, the state of the disease and its severity, the age of the patient to be treated, and the like.

^{"Prodrug" refers to compounds that are transformed} in vivo ^{to produce a biologically active compound,} particularly the parent compound, for example, by hydrolysis in the intestine or enzymatic conversion. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, esters of phosphate groups and carboxylic acids, such as aliphatic esters, particularly alkyl esters (eg, C _1-6 alkyl esters). Other prodrug moieties include phosphate esters such as -CH ² -OP(O)(OR ^')2 or a salt thereof, where R' is H or C ¹ -6 alkyl. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to, benzyl. Examples of pharmaceutically acceptable amides of the compounds described herein include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (eg, with between about one and about six carbons). Amides and esters of the described exemplary embodiments of the compounds according to the present invention may be prepared according to conventional methods. A detailed discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series and in Bioreversible Carriers in Drug Design, ed., Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

"Solvate" refers to a complex formed by the combination of solvent molecules with molecules or ions of a solute. The solvent can be an organic solvent, an inorganic solvent, or a mixture of both. Exemplary solvents include, but are not limited to, alcohols, such as methanol, ethanol, propanol; amides, such as N,N-dialiphatic amides, such as N,N-dimethylformamide; tetrahydrofuran; alkyl sulfoxides, such as dimethyl sulfoxide; water; and combinations thereof. The compounds described herein can exist in unsolvated as well as solvated forms when combined with solvents, pharmaceutically acceptable or not, such as water, ethanol, and the like. Solvated forms of the compounds described herein are within the scope of the embodiments described herein.

"Sulfonamide" refers to the group or moiety -SO ₂ amino, or -N(R)sulfonyl, where R is H, aliphatic, heteroaliphatic, cyclic, heterocyclic, including aromatic, both aryl and heteroaryl.

"Sulfanyl" refers to the group o -SH, -S-aliphatic, -S-heteroaliphatic, -S-cyclic, -S-heterocyclyl, including -S-aromatic, both -S-aryl and -S-heteroaryl.

"Sulfinyl" refers to the group or moiety -S(O)H, -S(O)aliphatic, -S(O)heteroaliphatic, -S(O)cyclic, -S(O)heterocyclyl, including aromatic, both -S(O)aryl as -S(O)heteroaryl.

"Sulfonyl" refers to the group: -SOzH, -SO ₂ aliphatic, -SO ₂ heteroaliphatic, -SO ₂ cyclic, -SO ₂ heterocyclyl, including aromatic sulfonyls, including both -SO ₂ aryl and -SO ₂ heteroaryl.

"Treating" or "treatment" as used herein refers to the treatment of a disease or condition of interest in a patient or subject, in particular a human suffering from the disease or condition of interest, and includes, by way of example, and without limitation:

(i) prevent the disease or condition from occurring in a patient or subject, in particular, where said patient or subject is predisposed to the condition but has not yet been diagnosed as having it;

(ii) inhibit the disease or condition, for example by stopping or slowing its development;

(iii) alleviate the disease or condition, for example, by causing regression of the disease or condition or a symptom thereof; either

(iv) stabilize the disease or condition.

As used herein, the terms "disease" and "condition" may be used interchangeably or may be different in the sense that the particular disease or condition may not have a known causative agent (so it has not yet been determined). determined the etiology) and, therefore, it is not yet recognized as a disease, but only as an undesirable condition or syndrome, in which doctors have identified a more or less specific set of symptoms.

The above definitions and the following general formulas are not intended to include impermissible substitution patterns (eg, methyl substituted with 5 fluoro groups). Impermissible substitution patterns of this type are readily recognized by one of ordinary skill in the art.

Any of the groups referred to herein may be optionally substituted with at least one, possibly two or more substituents as defined herein. That is, a substituted group has at least one, possibly two or more, substitutable hydrogens replaced by a substituent(s) as defined herein, unless the context otherwise indicates or a particular structural formula precludes substitution.

One of ordinary skill in the art will appreciate that the compounds may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and/or optical isomerism. For example, certain described compounds may include one or more chiral centers and/or double bonds and, as a consequence, may exist as stereoisomers, as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof such as racemic mixtures. As another example, certain disclosed compounds can exist in various tautomeric forms, including the enol form, the keto form, and mixtures thereof. As the various compound names, formulas, and drawings of compounds within the specification and claims may represent only one of the possible tautomeric, conformational isomeric, optical isomeric, or geometric isomeric forms, one of ordinary skill in the art will appreciate that compounds described encompass any tautomeric, conformational isomeric, optical isomeric, and/or geometric isomeric forms of the compounds described herein, as well as mixtures of these various different isomeric forms. In cases of limited rotation, e.g. eg around the amide bond or between two directly attached rings, such as pyrazolyl and pyridinyl rings, atropisomers are also possible and are also specifically included in the compounds of the invention.

In any embodiment, any or all of the hydrogens present in the compound, or in a particular group or moiety within the compound, may be replaced by a deuterium or a tritium. Thus, a listing of alkyl includes deuterated alkyl, where from one to the maximum number of hydrogens present can be replaced by deuterium. For example, ethyl can be C ² H ⁵ or C ² H ⁵ , where 1 to 5 hydrogens are replaced by deuterium such as in C ² DxHs-x.

II. Compounds with IRAK Activity and Compositions Comprising Compounds with IRAK Activity A. Amide compounds

Amide compounds, methods of preparing the compounds, and methods of using the compounds are described herein. In one embodiment, the disclosed compounds are tyrosine kinase inhibitors. In a particular embodiment, the compounds are useful for blocking one or more cytokine signaling pathways, such as the IL-17 signaling pathway. For certain embodiments, the amide compounds are useful for treating conditions in which inhibition of an interleukin-1 receptor-associated kinase (IRAK) pathway is therapeutically useful. In some embodiments, the compounds directly inhibit an IRAK protein, such as IRAK1, IRAK ₂ , IRAK3, IRAK4, or a combination thereof.

Exemplary amide compounds within the scope of the present invention have a general formula 1

One skilled in the art will appreciate that salts, N-oxides and/or solvates, including hydrates, of such compounds may also be formed, and accordingly, it is understood that salts, N-oxides and/or solvates are included within the scope of the general formulas described 1 -9.

Referring to formula 1, ring A is heteroaryl. In some embodiments, ring A is pyridinyl or pyrazinyl. In some embodiments, ring A is

wherein each Q is independently CH, CRm, or N, Rm is Rb, and x is 0, 1, or 2; and at least one of Q is N.

Ra is independently, for each occurrence, H, D, C _1-6 alkyl, C _3-6 cycloalkyl, C _5-10 aromatic, or C _3-6 heterocycloaliphatic;

Rb is independently, for each occurrence, -OH, -CF ³ , -CN, -ORc, -SO ₂ Rc, -NRdRd, -N(H)SO ₂ Rc, -C(O)OH, -N(H) C(O)Rc, -C(O)ORc, -C(O)NRdRd, =O, or halogen;

Rc is independently, for each occurrence, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heteroalicyclyl, aralkyl, C _1-6 alkyl substituted with 1,2 or 3 Re, C ₅ aromatic _-10 , C _5-10 aromatic substituted with 1,2 or 3 Re;

Rd is independently, for each occurrence, H, C _1-6 alkyl optionally substituted with 1, 2 or 3 Re, C _3-6 cycloalkyl optionally substituted with 1, 2 or 3 Re, C _3-6 heteroalicyclyl optionally substituted with 1,2 or 3 Re, C _5-10 aromatic optionally substituted with 1,2 or 3 Ra or Rb, or two Rd groups, together with the nitrogen attached to it, form an optionally substituted C _3-6 heteroalicyclyl moiety with C _1-6 alkyl and optionally interrupted with one or two -O- or -N(R ₈ ), where R ₉ is R ₇ 0; and

Re is independently, for each occurrence, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, or -ORa. In some embodiments, ring A is

R1 is H, or Ci-6. In particular embodiments, R1 is H.

R2 is H; aliphatic, including alkyl, alkenyl, alkynyl, and cycloaliphatic, such as cycloalkyl; heteroaliphatic; or heterocyclyl. In some embodiments, R 2 is H, C _3-6 cycloalkyl, heterocycloaliphatic, such as 3-6 membered heterocycloaliphatic, or heteroaliphatic, such as 3-10 membered heteroaliphatic.

In some embodiments, R 2 is H, C _1-6 alkyl, heteroaliphatic, such as 3 to 10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy substituted cyclohexyl and/or hydroxy, unsubstituted C _1-6 alkyl, or C _1-6 alkyl substituted with -OH, amino, alkoxy, or heterocycloaliphatic.

In some embodiments, R2 is Ra, Ra substituted with Rb, Ra substituted with 1 or 2 Rc, or Ra substituted with Rd. R2 can be H, CH ₃ ,

In particular embodiments, ring A is pyridinyl or pyrazinyl; R1 is H; and R2 is H, heteroaliphatic, such as 3 to 10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy and/or hydroxy substituted cyclohexyl, unsubstituted C _1-6 alkyl, or C _1-6 alkyl substituted with -OH, amino, alkoxy, or heterocycloaliphatic.

With respect to formula 1, ring A can be: 1B) heteroaryl; 1E) pyridinyl; 1F) pyrazinyl; 1J) pyridin-2-yl; 1K) pyrazin-2-yl; 1L) 5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl; 1M) 5-oxetan-3-yloxypyridin-2-yl; 1N) 5-morpholinopyridin-2-yl; 1O) 5-(4-methylpiperazin-1-yl)pyridin-2-yl; 1P) 3,5-difluoropyridin-2-yl; or 1Q) 5-methoxypyridin-2-yl.

With respect to ring A of embodiments 1B to 1Q, R2 may be, in any combination with 1B to 1Q: 2A) H; 2B) aliphatic; 2C) heteroaliphatic; 2D) heterocycloaliphatic; 2E) C _1-6 alkyl; 2F) methyl; 2G) isopropyl; 2H) 2-morpholinoethyl; 2I) 2-(4-methylpiperazin-1-yl)ethyl; 2J) 2-hydroxyethyl; 2K) 2-(2-methoxyethoxy)ethyl; 2L) 2-methoxycyclobut-1-yl; 2M) 4-tetrahydropyran; 2N) 2-methoxyethyl; _2O ) 3-methoxypropyl; 2P) (1r,4r)-4-ethoxycyclohex-1-yl; 2Q) oxetan-3-yl; 3R) 1,3-dihydroxypropan-2-yl; or 2S) 2-(N,N-diethylamino)ethyl.

One of ordinary skill in the art will understand that any of 2A to 2S can be combined with any of 1B to 1Q to form any and all combinations between these substituents.

Each Z1, Z2, Z3, and Z4, is independently N or CR3, wherein at least one of Z1, Z2, Z3, and Z4 is N. Each R3 is independently H, aliphatic, or heteroaliphatic, and can be H or alkyl, such as H or C _1-6 alkyl. In some embodiments, each R3 is H. In some embodiments, one of Z1, Z2, Z3, and Z4 is N, and the remainder are CR3. In other embodiments, two of Z1, Z2, Z3, and Z4 are N, and the remainder are CR3. In some embodiments, the rest

is pyridinyl, pyrimidinyl, or pyrazinyl. In particular embodiments, Z1 is N, and Z2, Z3, and Z4 are CR3; both Z1 and Z2 are N, and Z3 and Z4 are CR3; both Z1 and Z3 are N, and Z2 and Z4 are CR3; both Z1 and Z4 are N, and Z2 and Z3 are CR3; or Z3 is N, and Z1, Z2, and Z4 are CR3. In any of these embodiments, ring A is pyridinyl or pyrazinyl; R1 is H; and R2 is H, heteroaliphatic, such as 3 to 10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy and/or hydroxy substituted cyclohexyl, unsubstituted C _1-6 alkyl , or C _1-6 alkyl substituted with -OH, amino, alkoxy, or heterocycloaliphatic.

In particular embodiments, Z1 is N, and Z2, Z3, and Z4 are CR3; both Z1 and Z2 are N, and Z3 and Z4 are CR3; both Z1 and Z3 are N, and Z2 and Z4 are CR3; both Z1 and Z4 are N, and Z2 and Z3 are CR3; or Z3 is N, and Z1, Z2, and Z4 are CR3. In any of these embodiments, ring A is pyridinyl or pyrazinyl; R1 is H; R2 is H, heteroaliphatic, such as 3 to 10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy and/or hydroxy substituted cyclohexyl, unsubstituted C _1-6 alkyl, or C _1-6 alkyl substituted with -OH, amino, alkoxy, or heterocycloaliphatic; and each R3 is H.

In any of the embodiments of formula 1, R4 can be halogen, heterocycloaliphatic, aryl, heteroaryl, -NH-heteroaryl, or -O-heteroaryl. R4 can be halogen, such as Br; 5 to 10 membered heteroaryl, 3 to 6 membered heterocycloaliphatic, 6 to 10 membered aryl, -NH-(5 to 10 membered heteroaryl), or -O-(5 to 10 membered heteroaryl). And in some embodiments, R4 is halogen, pyridinyl pyrimidinyl, pyrazolyl, -NH-pyrazolyl, pyrrolyl, -O-pyridinyl, -NH-pyridinyl indolyl, furanyl, -NH-benzopyrazolyl, pyrrolopyridinyl phenyl, tetrahydropyridinyl piperidinyl, or 2-oxo-1 ,2-dihydropyridinyl.

R4 can be Br,

wherein y is 0, 1, or 2, and each Rp is independently Ra, Rb, Ra substituted with Rb, or Ra substituted with Rc. In certain embodiments, each Rp is independently -CH ³ , -OCH ³ , -NH ² , -CF ³ , F, -CN,

In particular embodiments, Z1 is N, and Z2, Z3, and Z4 are CR3; both Z1 and Z2 are N, and Z3 and Z4 are CR3; both Z1 and Z3 are N, and Z2 and Z4 are CR3; both Z1 and Z4 are N, and Z2 and Z3 are CR3; or Z3 is N, and Z1, Z2, and Z4 are CR3. In any of these embodiments, ring A is pyridinyl or pyrazinyl; R1 is H; R2 is H, heteroaliphatic, such as 3 to 10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy and/or hydroxy substituted cyclohexyl, unsubstituted C _1-6 alkyl, or C _1-6 alkyl substituted with -OH, amino, alkoxy, or heterocycloaliphatic; each R3 is H; and R4 is Br; unsubstituted pyridinyl; C _1-6 alkyl-substituted pyridinyl, haloalkyl, amino, heterocycloaliphatic, cycloalkyl, -CN, alkoxy, -O-heterocycloaliphatic, -NH-heterocycloaliphatic, halogen, sulfonamide, -O-benzyl, carboxyl, sulfonyl, -NH-cycloalkyl , or amide; unsubstituted pyrimidinyl; pyrazolyl not substituted; Ci-e alkyl substituted pyrazolyl; -NH-pyrazolyl unsubstituted; -NH-pyrazolyl substituted with C1-6 alkyl, or heteroaryl; pyrrolyl; -O-pyridinyl unsubstituted; -O-pyridinyl substituted with amino; -NH-pyridinyl substituted with Ci-6 alkyl, haloalkyl, or heterocycloaliphatic; unsubstituted indolyl; alkoxy substituted indolyl; furanyl; -NH-benzopyrazolyl; pyrrolopyridinyl; unsubstituted phenyl; phenyl substituted with halogen, C1-6 alkyl, alkoxy, -CN, amino, or sulfonamide; unsubstituted tetrahydropyridinyl; tetrahydropyridinyl substituted with tert-butoxycarbonyl; piperidinyl; or 2-oxo-1,2-dihydropyridinyl.

With respect to formula 1, R4 can be, in any combination with ring A embodiments 1B to 1Q, R2 embodiments 2A to 2S, and R1 being H: 3A) halogen; 3B) heterocyclyl; 3C) aryl; 3D) heteroaryl; 3E) heterocycloaliphatic; 3F) 5-membered heteroaryl; 3G) 6-membered heteroaryl; 3H) pyridinyl; 3I) pyrimidinyl; 3J) pyrazolyl; 3K) pyrrolyl; 3L) indolyl; 3M) pyrazolopyridinyl; 3N) furanyl; 3O) -NH-heteroaryl; 3P) -O-heteroaryl; 3Q) tetrahydropyridinyl; 3R) bromine; 3S) pyridin-3-yl; 3T) 3-fluoropyridin-3-yl; 3U) 5-cyanopyridin-3-yl; 3V) pyrimidin-5-yl; 3W) ^{1H-pyrazol-5-yl; 3X) 3-methyl-1H-pyrazol-5-yl; 3Y) 1 -methyl-1 H -pyrazol-4-yl; 3Z) 1H-pyrazol-4-yl; 3AA) 1H-pyrrol-2-yl;} 3 ^to B) ^{1H-pyrrol-3-yl;} 3 ^to C) ^{5-methylpyridin-3-yl; 3AD) 5-cyclopropylpyridin-3-yl;} 3 ^to E) ^{5-trifluoromethylpyridin-3-yl; 3AF) 2-} trifluoromethylpyridin-4-yl; 3AG) 5-methoxypyridin-3-yl; 3AH) 2-methoxypyridin-5-yl; 3AI) 2-methoxypyridin-4-yl; 3AJ) 5-isopropoxypyridin-3-yl; 3AK) 5-((tetrahydro-2H-pyran)oxy)pyridin-3-yl; 3AL) 5-(2,2,2-trifluoroethoxy)pyridin-3-yl; 3AM) 5-aminopyridin-3-yl; 3AN) 5-(methylamino)pyridin-3-yl; 3AO) 5-(cyclopropylamino)pyridin-3-yl; 3AP) 5-(isopropylamino)pyridin-3-yl; 3AQ) 5-(tert-butylamino)pyridin-3-yl; 3AR) 5-((tetrahydro-2H-pyran)amino)pyridin-3-yl; 3AS) 5-((2-methoxyethyl)amino)pyridin-3-yl; 3AT) 5-((cyclopropylmethyl)amino)pyridin-3-yl; 3AU) 5-((2,2,2- ^{trifluoroethyl)amino)pyridin-3-yl; 3AV) 5-(methylsulfonamido)pyridin-3-yl; 3AW) 5-(dimethylamino)pyridin-3-yl;} 3A ^x ) ^5- (pyrrolidin-1-yl)pyridin-3-yl; 3AY) 5-(morpholino)pyridin-3-yl; 3AZ) 5-(4-methylpiperazin-1-yl)pyridin-3-yl; 3BA) 5-methylsulfonylpyridin-3-yl; 3BB) 5-carbamoylpyridin-3-yl; 3BC) 2-carbamoylpyridin-4-yl; 3BD) 2-cyanopyridin-4-yl; 3BE) 6- ^{aminopyridin-3-yl; 3BF) 1H-pyrrolo[2,3-b]pyridin-5-yl; 3BG) 1H-pyrrolo[3,2-b]pyridin-6-yl; 3b} H) ^{1H-indol-5-yl; 3BI)} 1 ^{h -indol-6-yl; 3BJ) phenyl; 3BK) m-tolyl; 3b} L) ^{p-tolyl; 3BM) 3-methoxyphenyl; 3b} N) ^{4-methoxyphenyl; 3BO) 3-cyanophenyl; 3BP)} 4-cyanophenyl; 3BQ) 3-fluorophenyl; 3BR) 4-fluorophenyl; 3BS) 3-aminophenyl; 3BT) 3-(methylamino)phenyl; 3BU) 3-(dimethylamino)phenyl; 3BV) 3-(methylsulfonamido)phenyl; 3BW) 1'-(tert-butoxycarbonyl)-1',2',3',6'-tetrahydropyridin-4-yl; 3BX) 1',2',3',6'-tetrahydropyridin-4-yl; 3BY) piperazin-4-yl; 3BZ) 1'-(tert-butoxycarbonyl)-1',2',3',6'-tetrahydropyridin-3-yl; 3CA) 1',2',3',6'-tetrahydropyridin-3-yl; 3CB) 3-methyl-1H-pyrazol-4-yl; 6CC) pyridin-4-yl; 3CD) pyridin-4-yloxy; 3CE) 2-oxo-1,2-dihydropyridin-4-yl; 3CF) 6-oxo-1,6-dihydropyridin-3-yl; 3CG) 6-acetamidopyridin-3-yl; 3CH) 1-(cyclopropylmethyl)-1H-pyrazol-4-yl; 3CI) 1H-pyrazol-3-yl; 3CJ) (1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)amino; 3CK) (1 H-pyrazol-3-yl)amino; 3CL) ^{(3-methyl-1H-pyrazol-4-yl)amino; 3CM) 5-carboxypyridin-3-yl;} 3C ⁿ ) ^{3-fluoropyridin-4-yl; 3CO) 3-methylpyridin-4-yl; 3CP) 2-methylpyridin-4-yl; 3CQ) 6-methoxy-1H-indol-2-yl; 3CR) furan-3-yl; 3CS) furan-2-yl; 3CT) (1H-indazol-5-yl)amino;} 3C ^u ) (2H-indazol-5-yl)amino; 3CV) 5-(2-hydroxypropan-2-yl)pyridin-3-yl; 3CW) 2-methylpyridin-4-yl; 3CX) 2-methylpyridin-5-yl; 3CY) (2-aminopyridin-4-yl)oxy; 3CZ) (2,5-dimethylpyridin-4-yl)amino; 3DA) (6-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)amino; 3DB) 2-((cyclopropylmethyl)amino)pyridin-4-yl; or 3DC) 2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl.

One skilled in the art will understand that any of 3A to 3DC can be combined with any of 1B to 1Q, any of 2A to 2FS, and R1 being H, to form any and all combinations between such substituents. With respect to ring A embodiments 1B to 1Q, R2 embodiments 2A to 2S, R4 embodiments 3A to 3DC, and R1 being hydrogen, Z1, Z2, Z3 and Z4 may be, in any combination with 1B to 1Q , 2A to 2S, and 3A to 3DC: 4A) Z1 is N and Z2, Z3 and Z4 are CH; 4B) Z1 and Z2 are N and Z3 and Z4 are CH; 4C) Z1 and Z3 are N and Z2 and Z4 are CH; 4D) Z1 and Z4 are N and Z2 and Z3 are CH; or 4E) Z3 is N and Z1, Z2 and Z4 are CH.

One skilled in the art will understand that any of 4A to 4E can be combined with any of 1B to 1Q, any of 2A to 2S, any of 3A to 3DC, and R1 being H, to form any and all combinations between such substituents.

In some embodiments of formula 1, the compound has formula 2

With reference to formula 2, R1, R2, R4 and ring A are as defined for formula 1. R5, R6, and R7 are each independently H or alkyl, such as C _1-6 alkyl, and in certain embodiments, each of R5, R6, and _R7 is H.

In particular embodiments of formula 2, ring A is pyridin-2-yl or pyrazin-2-yl; R1 is H; R2 is H, heteroaliphatic, such as 3-10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, alkoxy-substituted cyclobutyl and/or hydroxy, cyclohexyl, alkoxy-substituted cyclohexyl and/or hydroxy, unsubstituted Ci-6 alkyl, or -OH, amino, alkoxy, or heterocycloaliphatic substituted Ci-6 alkyl; each R3 is H; and R4 is Br; unsubstituted pyridinyl; C _1-6 alkyl-substituted pyridinyl, haloalkyl, amino, heterocycloaliphatic, cycloalkyl, -CN, alkoxy, -O-heterocycloaliphatic, -NH-heterocycloaliphatic, halogen, sulfonamide, -O-benzyl, carboxyl, sulfonyl, -NH-cycloalkyl , or amide; unsubstituted pyrimidinyl; unsubstituted pyrazolyl; pyrazolyl substituted with C _1-6 alkyl; -NH-pyrazolyl unsubstituted; -NH-pyrazolyl substituted with C _1-6 alkyl, or heteroaryl; pyrrolyl; -O-pyridinyl unsubstituted; -O-pyridinyl substituted with amino; -NH-pyridinyl substituted with C _1-6 alkyl, haloalkyl, or heterocycloaliphatic; unsubstituted indolyl; alkoxy substituted indolyl; furanyl; -NH-benzopyrazolyl; pyrrolopyridinyl; unsubstituted phenyl; phenyl substituted with halogen, C ¹ -6 alkyl, alkoxy, -CN, amino, or sulfonamide; unsubstituted tetrahydropyridinyl; tetrahydropyridinyl substituted with tert-butoxycarbonyl; piperidinyl; or 2-oxo-1,2-dihydropyridinyl.

With respect to formula 2, one skilled in the art will understand that when R1, R5, R6, and _R7 are H, any of the embodiments 1B to 1Q of ring A, can be combined with any of the embodiments 2A to 2S of R2, and any of the embodiments 3A to 3DC of R4 to form any and all combinations between such substituents.

In some embodiments of formulas 1 and 2, ring A is pyridinyl, such as pyridin-2-yl; or pyrazinyl, such as pyrazin-2-yl. In particular embodiments, such compounds, or salts, solvates, hydrates, have a formula 3

With respect to formula 3, R1, R2, R3, R4, Z1, Z2, Z3, and Z4 are as defined for formulas 1 and 2. R8, R9, R10, and R11 are each independently H, aliphatic, halogen, heterocycloaliphatic, alkoxy, or -O-heterocycloaliphatic. Each of R ₈ , R 9 , R 10 and R 11 can independently be H, halogen, 3 to 6 membered heterocycloaliphatic, alkoxy, or -O-(3 to 6 membered heterocycloaliphatic). In some embodiments, R9 and R11 are H, _R8 is H or halogen, such as F, and R10 is halogen, such as F, 3- to 6-membered heterocycloaliphatic, such as morpholino or N-methylpiperidinyl, alkoxy, such as methoxy. or 2-hydroxy-2-methylpropoxy, or -O-oxetanyl. In some embodiments, _R8 , R9, R10, and R11 are each H. In other embodiments, _R8 , R9, and R11 are H, and R10 is 3- to 6-membered heterocycloaliphatic, such as morpholino or N-methylpiperidine- 1-yl; alkoxy, such as methoxy or 2-hydroxy-2-methylpropoxy; u -O-oxetanyl. In certain other embodiments, R9 and R11 are H, and _R8 and R10 are F.

In particular embodiments, Z1 is N, and Z2, Z3, and Z4 are CR3; both Z1 and Z2 are N, and Z3 and Z4 are CR3; both Z1 and Z3 are N, and Z2 and Z4 are CR3; both Z1 and Z4 are N, and Z2 and Z3 are CR3; or Z3 is N, and Z1, Z2, and Z4 are CR3. In any of these embodiments, R1 is H; R2 is H, heteroaliphatic, such as 3 to 10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy and/or hydroxy substituted cyclohexyl, unsubstituted C _1-6 alkyl, or C _1-6 alkyl substituted with -OH, amino, alkoxy, or heterocycloaliphatic; each R3 is H; R ₈ is H or F; R9 is H; R10 is H, F, 3- to 6-membered heterocycloaliphatic, such as morpholino or N-methylpiperidinyl, alkoxy, such as methoxy or 2-hydroxy-2-methylpropoxy, or -O-oxetanyl; and R11 is H.

In some embodiments of formula 3, the compound has formula 4

With respect to Formula 4, R1, R2, R3, R4, _R8 , R9, R10, and R11 are as defined for Formula 3, and Z5 and Z6 are independently N or CR3, provided that at least one of Z5 and Z6 are CR3. In some embodiments, both Z5 and Z6 are CR3. In other embodiments, Z5 is N and Z6 is CR3, and in alternate embodiments, Z5 is CR3 and Z6 is N. In some embodiments, the compound has a formula selected from

With respect to Formulas 5, 6, and 7, R1, R2, R4, _R8 , R9, R10, and R11 are as defined for Formula 4.

In certain embodiments of formula 3, the compound has formula 8

Referring to Formula 8, R1, R2, R4, _R8 , R9, R10, and R11 are as defined for Formula 3, and R5, R6, and _R7 are each independently H or alkyl, such as C _1-6 alkyl. In certain embodiments, each of R5, R6, and R7 is H, leading to compounds having formula 9

In particular embodiments of formulas 8 and 9, R1 is H; R2 is H, heteroaliphatic, such as 3 to 10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy and/or hydroxy substituted cyclohexyl, unsubstituted C _1-6 alkyl, or C _1-6 alkyl substituted with -OH, amino, alkoxy, or heterocycloaliphatic; R4 is Br; unsubstituted pyridinyl; C _1-6 alkyl-substituted pyridinyl, haloalkyl, amino, heterocycloaliphatic, cycloalkyl, -CN, alkoxy, -O-heterocycloaliphatic, -NH-heterocycloaliphatic, halogen, sulfonamide, -O-benzyl, carboxyl, sulfonyl, -NH-cycloalkyl , or amide; unsubstituted pyrimidinyl; unsubstituted pyrazolyl; pyrazolyl substituted with C _1-6 alkyl; -NH-pyrazolyl unsubstituted; -NH-pyrazolyl substituted with C _1-6 alkyl, or heteroaryl; pyrrolyl; -O-pyridinyl unsubstituted; -O-pyridinyl substituted with amino; -NH-pyridinyl substituted with C _1-6 alkyl, haloalkyl, or heterocycloaliphatic; unsubstituted indolyl; alkoxy substituted indolyl; furanyl; -NH-benzopyrazolyl; pyrrolopyridinyl; unsubstituted phenyl; phenyl substituted with halogen, C _1-6 alkyl, alkoxy, -CN, amino, or sulfonamide; unsubstituted tetrahydropyridinyl; tetrahydropyridinyl substituted with tert-butoxycarbonyl; piperidinyl; or 2-oxo-1,2-dihydropyridinyl; R ₈ is H or F; R9 and R11 are H; and R10 is H; F; 3 to 6 membered heterocycloaliphatic, such as morpholino or N-methylpiperidinyl; alkoxy, such as methoxy or 2-hydroxy-2-methylpropoxy; u -O-oxetanyl. And in certain embodiments, each of R ₈ , R 9 , R 10 and R 11 is H; R ₈ , R 9 , and R 11 are H and R 10 is 3- to 6-membered heterocycloaliphatic, such as morpholino or N-methylpiperidinyl, alkoxy, such as methoxy or 2-hydroxy-2-methylpropoxy, or -O-oxetanyl, R ₈ and R10 are F, and R9 and R11 are H.

Certain exemplary described compounds within the scope of one or more of General Formulas 1-9 include:

Exemplary compounds described within the scope of one or more of General Formulas 1-9 include:

I-1: 6-bromo-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-2: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

I-3: 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

I-4: 5'-cyano-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

I-5: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(pyrimidin-5-yl)picolinamide;

I-6: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-5-yl)picolinamide;

I-7: 6-(3-methyl-1H-pyrazol-5-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-8: 6-(1-methyl-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

1-9: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-10: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(1 H-pyrazol-2-yl)picolinamide;

I-11: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)picolinamide;

I-12: 5'-methyl-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

I-13: 5'-cyclopropyl-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

I-14: 5'-(2-hydroxypropan-2-yl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'- bipyridine]-6-carboxamide; I-15: 2'-methyl-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide;

I-16: 6'-methyl-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

I-17: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(trifluoromethyl)-[2,3'-bipyridine]-6-carboxamide ;

I-18: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-(trifluoromethyl)-[2,4'-bipyridine]-6-carboxamide ;

I-19: 5'-methoxy N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

I-20: 6'-methoxy-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

I - 21 : 2 '-me to x iN -(1 -me til-3 -(p ir id in -2 - il) -1 H -p ira zo l-4 - il) -[2 ,4 '- b ip ir id in ]-6 -ca rb oxam id a ;

I-22 : 5 '- is o prop o x i-N -(1 -m e ti l-3 -(p ir id in -2 - i l) -1 H -p ira z o l-4 - i l) -[2 ,3 '-b ip ir id in ]-6 -c a rb o x a m id a ;

I-23: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-((tetrahydro-2H-pyran-4-yl)oxy)-[ 2,3'-bipyridine]-6-carboxamide; I-24: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5'-(2,2,2-trifluoroethoxy)-[2,3'-bipyridine ]-6-carboxamide;

I-25: 5'-amino-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

I-26: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(methylamino)-[2,3'-bipyridine]-6-carboxamide ;

I-27: 5'-(cyclopropylamino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide ;

I-28: 5'-(isopropylamino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide ;

I-29: 5'-(tert-butylamino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]-6 -carboxamide;

I-30: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5'-((tetrahydro-2H-pyran-4-yl)amino)-[2 ,3'-bipyridine]-6-carboxamide;

I-31: 5'-((2-methoxyethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin ]-6-carboxamide;

I-32: 5'-((cyclopropylmethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide; I-33: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-((2,2,2-trifluoroethyl)amino)-[2, 3'-bipyridine]-6-carboxamide; I-34: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(methylsulfonamido)-[2,3'-bipyridine]-6-carboxamide ;

I-35: 5'-(dimethylamino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide ;

I-36: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(pyrrolidin-1-yl)-[2,3'-bipyridin] -6-carboxamide;

I-37: N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-5'-morpholino-[2,3'-bipyridine]-6-carboxamide;

I-38: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(4-methylpiperazin-1-yl)-[2,3'- bipyridine]-6-carboxamide;

I-39: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(methylsulfonyl)-[2,3'-bipyridine]-6-carboxamide ;

I-40: N6-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-5',6-dicarboxamide;

I-41: N6-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-2',6-dicarboxamide;

I-42: 2'-cyano-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide;

I-43: 6'-amino-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

I-44: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl )picolinamide;

I-45: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrrolo[3,2-b]pyridin-6-yl )picolinamide;

I-46: 6-(1H-indol-5-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-47: 6-(1H-indol-6-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

I-48: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-phenylpicolinamide;

I-49: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(m-tolyl)picolinamide;

I-50: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(p-tolyl)picolinamide;

I-51: 6-(3-methoxyphenyl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide;

I-52: 6-(4-methoxyphenyl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide;

I-53: 6-(3-cyanophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide;

I-54 : 6 -(4 -c ia no fen il) -N -(1 -methyl-3 -(p ir id in -2 - il) -1 H -p ira zo l-4 - il) pico linamida ;

-55 : 6 -(3 - fluoro phenyl) -N -(1 -m e til-3 -(p ir id in -2 - il) -1 H -p ira z o l-4 - i l)p ic o lin a m id a ;

-56: 6-(4-fluorophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide;

-57: 6-(3-aminophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide;

-58: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(3-(methylamino)phenyl)picolinamide;

-59: 6-(3-(dimethylamino)phenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

-60: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(3-(methylsulfonamido)phenyl)picolinamide;

-61 -((1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)carbamoyl)-3',6'-dihydro-[2,4'-bipyridin]-1' tert-butyl (2'H)-carboxylate;

-62: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-1',2',3',6'-tetrahydro-[2,4'- bipyridine]-6-carboxamide;

-63: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(piperidin-4-yl)picolinamide;

-64-((1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)carbamoyl)-5',6'-dihydro-[2,3'-bipyridin]-1' tert-butyl (2'H)-carboxylate;

-65: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-1',2',5',6'-tetrahydro-[2,3'- bipyridine]-6-carboxamide;

-66: 6-bromo-N-(3-(5-methoxypyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)picolinamide;

-67: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-5-yl)picolinamide;

-68: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

-69: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridine]-6-carboxamide;

-70: 5'-isopropoxy-N-(3-(5-methoxypyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)-[2,3'-bipyridin]-6-carboxamide;

-71: 5'-(isopropylamino)-N-(3-(5-methoxypyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)-[2,3'-bipyridin]-6- carboxamide; -78: 6-(3-methyl-1 H -pyrazol-4-yl)-N-(1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide;

-79: 6-bromo-N-(1-isopropyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide;

-80: N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

-81: N-(1-isopropyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridine]-6-carboxamide;

-82: 6-bromo-N-(1 -(2-morpholinoethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide;

-83: N-(1 -(2-morpholinoethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide;

-84: 5'-methyl-N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]-6- carboxamide;

-85: 6-bromo-N-(1 -(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide;

-86: N-(1 -(2-(4-methylpiperazin-1 -yl)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazole -4-yl)picolinamide;

-87: 5'-methyl-N-(1 -(2-(4-methylpiperazin-1 -yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2 ,3'-bipyridine]-6-carboxamide; -88: N-(1 -(2-hydroxyethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide;

-89: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(pyridin-4-yloxy)picolinamide;

-90: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridin]-6- carboxamide;

-91: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-oxo-1',2'-dihydro-[2,4'-bipyridine ]-6-carboxamide;

-92 : N -(1 -met il-3 -(p ir id in -2 - il) -1 H -p ira zo l-4 - il) -6 '-oxo -1 ',6 '- d ih id ro -[2,3 '-b ip ir id in ] -6 -ca rb oxam id a ;

-93 : N -(1 -m e til-3 -(p ira z in -2 - yl) -1 H -p ira z o l-4 - yl) -5 '-(2 ,2 ,2 - t r i fluo ro e to x i) -[2,3 '-b ip ir id in ] -6 -c a rb o x a m id a ;

-94: N-(3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide;

-95: N-(1 -(2-methoxyethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide;

-96: 2'-methoxy-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'- bipyridine]-6-carboxamide; -97: 6'-amino-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'- bipyridine]-6-carboxamide; -98: 6'-acetamido-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'- bipyridine]-6-carboxamide; -99: 2'-methoxy-N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide;

-100: N-(1-methyl-3-(pyrazin-2-yl)-1 H -pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide;

-101: N-(1-methyl-3-(pyrazin-2-yl)-1 H -pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

-102: 6'-acetamido-N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

-103: 2'-(benzyloxy)-N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide;

-104: N-(1 -(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide;

-105: N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-5'-(2,2,2-trifluoroethoxy)-[2,3' formate -bipyridine]-6-carboxamide;

-106: N-(3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide formate;

-107: N-(1 -(2-methoxyethyl)-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide formate;

-108: N-(1 -(2-hydroxyethyl)-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide formate;

-109: 5-(1 -(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)nicotinamide;

-110: N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-[3,4'-bipyridine]-5-carboxamide;

-111: N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-[3,3'-bipyridine]-5-carboxamide;

-112: N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

-113: 6-bromo-N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide;

-114: 5'-methyl-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide;

-115: 5'-(methylsulfonamido)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridin ]-6-carboxamide; -116: N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide;

-117: N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-3-yl)picolinamide;

-118: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-((1-methyl-3-(pyridin-2-yl)-1H -pyrazol-4-yl)amino)pyrimidine-2-carboxamide;

-119: (methylsulfonyl)(6-((1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)carbamoyl)-[2,3'-bipyridine sodium ]-5'-yl)amide;

-120: N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-4-(5-methylpyridin-3-yl)pyrimidine-2-carboxamide;

-121: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(5-methylpyridin-3-yl)pyrazine-2-carboxamide;

-122: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

-123 : N -(1 -me til-3 -(p ir id in -2 - il) -1 H -p ira zo l-4 - il) -6 -(1 H -p ira zo l-3 - il) p ira z in -2 -ca rb oxam id a ;

I-124 : N -(1 -m e til-3 -(p ir id in -2 - il) -1 H -p ira z o l-4 - il) -4 -(1 H -p ira z o l-4 -i l)p ir im id in -2 -c a rb o x a m id a ;

I-125: N-(1 -(1,3-dihydroxypropan-2-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide;

I-126: N-(1 -(1,3-dihydroxypropan-2-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3 '-bipyridine]-6-carboxamide; I-127: N-(1-(1,3-dihydroxypropan-2-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4 -yl)picolinamide;

I-128: 4-((1 H-pyrazol-3-yl)amino)-N-(1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)pyrimidin-2- carboxamide;

I-129: 4-((3-methyl-1H-pyrazol-4-yl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl) pyrimidine-2-carboxamide; I-130: 5'-isopropoxy-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridin] -6-carboxamide;

I-131: 5'-fluoro-N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin] -6-carboxamide;

I-132: N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(trifluoromethyl)-[2,3'- bipyridine]-6-carboxamide;

I-133: N6-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]-5',6 -dicarboxamide;

I-134: 6-(1-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4 -yl)picolinamide;

I-135: 6-((1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)carbamoyl)-[2,3'-bipyridin]- acid 5'-carboxylic;

I-136: 6-(3-methyl-1H-pyrazol-5-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4 -yl)picolinamide;

I-137: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)pyrimidine-4-carboxamide;

I-138: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-2-(1 H-pyrazol-3-yl)pyrimidine-4-carboxamide;

I-139: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(pyridin-4-yloxy) formate )picolinam ide; I-140: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4'-bipyridin] formate -6-carboxamide; I-141: 2'-methoxy-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4 formate '-bipyridine]-6-carboxamide;

I-142: 6'-amino-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2, 3'-bipyridine]-6-carboxamide;

I-143: 6'-acetamido-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2, 3'-bipyridine]-6-carboxamide;

I-144: 3'-fluoro-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2, 4'-bipyridine]-6-carboxamide;

I-145: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-3'-methyl-[2, 4'-bipyridine]-6-carboxamide;

I-146: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-methyl-[2, 4'-bipyridine]-6-carboxamide;

I-147: 6-(6-methoxy-1H-indol-2-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 formate H-pyrazol-4-yl)picolinamide;

I-148: 6-(1 -(3-chlorophenyl)-1H-pyrazol-4-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2- yl)-1 H-pyrazol-4-yl)picolinamide;

I-149: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2, 3'-bipyridine]-6-carboxamide;

I-150: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol- 3-yl)picolinamide; I-151: 6-(furan-3-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-2,2,2-trifluoroacetate -pyrazol-4-yl)picolinamide;

-152: 6-(furan-2-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H- 2,2,2-trifluoroacetate pyrazol-4-l)picolinamide;

-153: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-formate -yl)picolinamide; -154: 6-((1 H-indazol-5-yl)amino)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H- formate pyrazol-4-yl)picolinamide;

-155: 6-((2H-indazol-5-yl)amino)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazole formate -4-yl)picolinamide;

-156: 6-((2-aminopyridin-4-yl)oxy)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazole formate -4-yl)picolinamide;

-157: 6-((2,5-dimethylpyridin-4-yl)amino)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H formate -pyrazol-4-yl)picolinamide;

-158: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-((6-(4- methylpiperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)picolinamide;

-159: 2'-((cyclopropylmethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4'-bipyridin] formate -6-carboxamide;

-160: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide 2,2,2-trifluoroacetate ;

-161: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2'-((2,2,2-trifluoroethyl)amino)-[2, 4'-bipyridine]-6-carboxamide;

-162: N-(1 -(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridin]- formate 6-carboxamide;

-163: N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide formate; -164: 5'-methyl-N-(3-(pyridin-2-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-4-yl)-[2,3' -bipyridine]-6-carboxamide; -165: 6-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- il)picolinamide;

-166: 6-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- il)picolinamide;

-167: N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridin]-6 -carboxamide;

-168: N-(1 -(2-methoxyethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridin]-6- carboxamide;

-169: N-(1 -(3-methoxypropyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridin]-6- carboxamide;

-170: 5'-methyl-N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide;

-171: N-(1 -methyl-3-(5-morpholinopyridin-2-yl)-1 H -pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide;

-172: N-(1 -methyl-3-(5-morpholinopyridin-2-yl)-1 H -pyrazol-4-yl)-6-(1 H-pyrazol-3-yl)picolinamide;

-173: 5'-methyl-N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3 '-bipyridine]-6-carboxamide; -174: N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4 -yl)picolinamide;

-175: N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3 -yl)picolinamide;

-176: 5'-methyl-N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridin]-6- dihydrochloride carboxamide;

-177: 5'-methyl-N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-[2 dihydrochloride ,3'-bipyridine]-6-carboxamide;

-178: N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)-5'-methyl-[2,3 '-bipyridine]-6-carboxamide;

I-179 : N -(3 -(5 -(2 -h id ro x i-2 -m e tilp ro p o xi)p ir id in -2 - il) -1 -m e til-1 H -p ira z o l -4-il) -6 -(1H-pyrazol-4-il)picolinamide; I-180: N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1 -methyl-1 H-pyrazol-4-yl)-6-(1 H-pyrazol- 3-yl)picolinamide; I-181: 5'-methyl-N-(1-methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3' -bipyridine]-6-carboxamide; I-182: N-(1 -methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4- il)picolinamide;

I-183: N-(1 -methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-3- il)picolinamide;

I-184: N-(3-(3,5-difluoropyridin-2-yl)-1 -((1 r,4r)-4-ethoxycyclohexyl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide; I-185: 3'-fluoro-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4' -bipyridine]-6-carboxamide; I-186: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-3'-methyl-[2,4' -bipyridine]-6-carboxamide;

I-187: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-methyl-[2,4' -bipyridine]-6-carboxamide;

I-188: 6-(6-methoxy-1 H-indol-2-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H- pyrazol-4-yl)picolinamide; I-189: 6-(1 -(3-chlorophenyl)-1 H-pyrazol-4-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl) -1 H-pyrazol-4-yl)picolinamide;

I-190: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3' -bipyridine]-6-carboxamide;

I-191: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-3- il)picolinamide;

I-192: 6-(furan-3-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide ;

I-193: 6-(furan-2-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide ;

I-193: 6-(furan-2-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide ;

I-194: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4- il)picolinamide;

1-195: 6-((1 H-indazol-5-yl)amino)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazole -4-yl)picolinamide; I-196: 6-((2H-indazol-5-yl)amino)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol- 4-yl)picolinamide; I-197: 6-((2-aminopyridin-4-yl)oxy)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol- 4-yl)picolinamide; I-198: 6-((2,5-dimethylpyridin-4-yl)amino)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H- pyrazol-4-yl)picolinamide; I-199: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-((6-(4-methylpiperazine -1-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)picolinamide;

I-200: 2'-((cyclopropylmethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridin]- 6-carboxamide; I-201: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide;

I-202: N-(1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-((2,2,2 trifluoroethyl)amino)-[2,4 '-bipyridine]-6-carboxamide; I-203: N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridin]-6 -carboxamide;

I-204: N-(1 -(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-205: N-(1 -((1 r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol- 4-yl)picolinamide;

I-206: N-(1 -((1 r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2, 3'-bipyridine]-6-carboxamide; I-207: N-(1 -methyl-3-(pyrazin-2-yl)-1 H -pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide; either

I-208: 5'-methyl-N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide.

B. Summary

The described amide compounds can be prepared as exemplified below, and as will be understood by one skilled in the art of organic synthesis. An exemplary synthesis may include the following 1st reaction step according to Scheme 1.

Acetyl compound 2 is reacted with dimethylformamide dimethyl acetal 4 at a suitable reaction temperature, such as from about 85°C to about 130°C, to form intermediate 6. Intermediate 6 is then reacted with hydrazine hydrate 8 to form pyrazole compound 10. The reaction is carried out in a suitable solvent, for example an alcohol, such as ethanol, methanol or isopropanol, and is usually heated, such as under reflux.

A 2nd reaction step in the exemplary synthesis according to Scheme 2 is provided below.

Compound 10 is nitrated using a suitable nitrating reagent or reagent mixture 12 to form compound 14. Suitable nitrating conditions include reacting compound 10 with nitric acid, such as fuming nitric acid, optionally in the presence of sulfuric acid. Typically, compound 10 and nitric acid are slowly added to each other. Cooling, for example using an ice bath, may be used to maintain the reaction temperature within a suitable range such as about 0°C to less than 50°C, 0°C to 20°C, or 0°C. C up to 10°C. After the addition is complete, the reaction is allowed to proceed until substantially complete, and may be allowed to warm to room temperature to facilitate the reaction. Optionally, additional nitrating reagent, or a mixture of nitrating reagents, can be added to facilitate the reaction to proceed to completion. The reaction is then quenched such as by addition of water and/or ice, and the product is separated or extracted from aqueous and purified if necessary. Purification techniques suitable for purifying a product of any reaction described herein include, but are not limited to, crystallization, distillation, and/or chromatography.

Continuing with reference to Scheme 2, compound 14 is then reacted with compound 16 to form compound 18. Compound 16 comprises a desired R1 moiety and a suitable leaving group, LG. Suitable leaving groups include any group that acts as a leaving group to facilitate the addition of the R 1 moiety to compound 14. Suitable leaving groups include, but are not limited to halogens, typically bromo, chloro or iodo, and tosylate or mesylate groups. Compound 14 is reacted with compound 16 in a suitable solvent and typically in the presence of a base. Suitable solvents include any solvent that facilitates the reaction such as aprotic solvents. Suitable solvents include, but are not limited to, DMF (dimethylformamide), THF (tetrahydrofuran), DMSO (dimethylsulfoxide), acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA (dimethylacetamide), dioxane, N-methylpyrrolidone, or combinations thereof. . Suitable bases include any base that facilitates the reactions such as a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate or cesium carbonate. The reaction can proceed at room temperature, or the reaction mixture can be heated such as 50°C, 100°C or higher as required. Compound 18 is then isolated from the reaction mixture and purified if necessary.

Compound 18 is reacted with a suitable reducing agent 20 to reduce the nitro moiety to an amine. Suitable reducing agents include, but are not limited to: gaseous hydrogen in the presence of a catalyst such as as a palladium catalyst; a borohydride such as sodium borohydride, optionally in the presence of a catalyst such as a nickel catalyst; metallic zinc in acetic acid; or iron powder in water or water and acid. In certain embodiments, hydrogen gas is used in combination with a palladium on carbon catalyst and in a suitable solvent such as ethyl acetate or methanol. In some embodiments, a combination of reducing agents and/or techniques is used. For example, the reduction may initially be carried out using a first method that comprises a first reducing agent and/or technique, but results in a mixture of products. The first method can be repeated and/or a second method can be performed, comprising a second reducing agent and/or technique. Once the reaction is complete, as indicated by an analytical technique such as LC-MS, TLC, or HPLC, product compound 22 is isolated and purified if necessary.

An exemplary 3rd step reaction sequence according to Scheme 3 is provided below.

Compound 22 is reacted with carboxylic acid 24 to form amide 26. Carboxylic acid 24 can be activated by any suitable method, and can then be reacted with amine 22. Suitable activation methods include, but are not limited to forming the acid chloride such as by treatment with thionyl chloride; treatment with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and a base such as diisopropylethylamine (DIPEA); treatment with carbonyldiimidazole (CDI); or treatment with a carbodiimide such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

Amide 26 is then coupled with compound 28 to form compound 30 using any suitable coupling reaction to form a bond between two rings. In the example of Scheme 3, a boronic acid coupling using boronic acid 28 is shown, where the leaving group L ^g in compound 26 is typically bromo or iodo. Other suitable coupling functional groups include trialkyl tin or boronic esters. The coupling reaction typically proceeds in the presence of a suitable catalyst. For a boronic acid coupling, the catalyst is typically a palladium catalyst, such as PdCl ² (dppf) ² , Pd[P(Ph)a] ² Cl ² , palladium acetate and triphenylphosphine, or tetrakis(triphenylphosphine)palladium( 0) . The reaction is carried out in the presence of a base, such as sodium, potassium, or cesium carbonate, and is carried out in a suitable solvent or solvent mixture, such as dioxane, dioxane/water, or DME (dimethoxyethane)/ethanol/water. The reaction can be heated to a suitable temperature such as a temperature within the range greater than room temperature up to the boiling point of the selected solvent, such as 50°C to 125°C, typically about 100°C. C, and/or stirred for a suitable period of time, such as 1 hour to 3 days, 6 hours to 24 hours, or 12 hours to 18 hours, to allow the reaction to proceed to completion. Next, compound 30 is isolated from the reaction mixture and purified by a suitable technique.

An alternative exemplary synthesis may include the following 1st reaction step according to Scheme 4.

Compound 32 is nitrated using a suitable nitrating reagent, or reagent mixture 34, to form compound 36. Suitable nitrating conditions include reacting compound 32 with nitric acid, such as fuming nitric acid, optionally in the presence of acid. sulfuric. Typically, compound 32 and nitric acid are slowly added to each other. Cooling, for example using an ice bath, may be used to maintain the reaction temperature within a suitable range such as about 0°C to less than 50°C, 0°C to 20°C, or 0°C. C up to 10°C. After the addition is complete, the reaction is allowed to proceed until substantially complete, and may be allowed to warm to room temperature to facilitate the reaction. Optionally, additional nitrating reagent, or a mixture of nitrating reagents, can be added to facilitate the reaction to proceed to completion. The reaction is then quenched such as by the addition of water and/or ice, and the product is separated or extracted from the aqueous phase and purified if required. Purification techniques suitable for purifying a product of any reaction described herein include, but are not limited to, crystallization, distillation, and/or chromatography.

Continuing with reference to Scheme 4, compound 36 is then reacted with compound 38 to form compound 40. Compound 38 comprises a desired ring as described with reference to the general formulas, including, by way of example, a cyclobutyl, cyclopentyl or cyclohexyl ring, and a suitable leaving group, LG. Suitable leaving groups include any group that acts as a leaving group to facilitate ring addition to compound 36. Suitable leaving groups include, but are not limited to halogens, typically bromo, chloro or iodo, and tosylate or mesylate groups. Compound 36 is reacted with compound 38 in a suitable solvent and typically in the presence of a base. Suitable solvents include any solvent that facilitates the reaction such as aprotic solvents. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents, such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that facilitates the reaction such as a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate or cesium carbonate. The reaction can proceed at room temperature, or the reaction mixture can be heated such as at a temperature within the range of temperatures greater than room temperature up to the boiling point of the selected solvent, such as at 50°C, 100°C or higher, as required. Compound 40 is then isolated from the reaction mixture and purified if necessary.

Compound 40 is reacted with a suitable reducing agent 42 to reduce the carbonyl moiety to a hydroxyl group. Suitable reducing agents include, but are not limited to sodium borohydride, diisobutylaluminum hydride, or lithium aluminum hydride. The reaction is carried out in a suitable solvent to facilitate the reaction, such as an alcohol, in particular methanol or ethanol, THF or diethyl ether. The reaction can proceed at room temperature, or the reaction mixture can be heated such as above room temperature to the boiling point of the selected solvent, such as 50°C, 100°C or higher. Alternatively, the reaction mixture can be cooled as required, for example below 20°C, below 10°C or below 0°C. After the reaction is complete, as indicated by an analytical technique such as LC-MS, TLC or HPLC, product compound 44 is isolated and purified if necessary, by a suitable technique such as column chromatography. Alternatively or additionally compound 45 can be isolated.

Optionally, compound 44, and/or compound 45, can be reacted with compound 46 to form compound 48 and/or compound 49. Compound 46 comprises a desired Rx moiety and a suitable leaving group, LG. Suitable leaving groups include any group that will act as a leaving group to facilitate the addition of the Rx moiety to compound 44 and/or compound 45. Suitable leaving groups include, but are not limited to halogen, typically bromo, chloro or iodo, and tosylate or mesylate groups. Compound 44/45 is reacted with compound 46 in a suitable solvent and typically in the presence of a base or other reagent(s) that facilitate the reaction. Suitable solvents include any solvent that facilitates the reaction such as aprotic solvents. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents, such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases or reagents that facilitate the reaction include, but are not limited to, silver triflate, 2,6-di-t-butylpyridine, sodium hydride, or combinations thereof. Typically, compound 46 is slowly added to the reaction mixture. Cooling, such as by using an ice bath, may be used to maintain the reaction temperature within a suitable range, such as from about 0°C to less than 50°C, from 0°C to 20°C, or from 0°C. °C up to 10°C. Once the addition of 46 is complete, the reaction is allowed to proceed until the reaction is substantially complete and can be allowed to warm to room temperature, or the reaction can be warmed to a temperature within the range greater than room temperature until the boiling point of the selected solvent, such as 50°C, 100°C or higher, to facilitate the reaction. After the reaction is complete, as can be indicated by an analytical technique, such as LC-MS, TLC or HPLC, the product compound 48 and/or compound 49 is isolated and purified if necessary, by a suitable technique, such as chromatography on column.

Another exemplary synthetic route for compound 48 and/or compound 49 is illustrated in Scheme 5.

Referring to Scheme 5, compound 36 is dissolved in a suitable solvent with cooling and treated with a base such as sodium hydride. Suitable solvents include, but are not limited to, aprotic solvents, such as 1,4-dioxane, THF, DMF, acetonitrile, ether, or a combination thereof. Cyclohexyl compound 37, which has a 4-nitrobenzenesulfone (nosyl, or Nos) leaving group, is added, and the reaction is heated to a suitable temperature to facilitate a reaction, such as to a temperature within a range higher than the room temperature to the boiling point of the selected solvent, such as 50°C to 200°C or higher, typically 90°C to 150°C. The reaction can be stirred, such as by hand stirring or mechanical stirring. Additional compound 37 can be added if necessary to facilitate the reaction to proceed to completion.

The reaction mixture is quenched such as by adding sodium bicarbonate solution, and the products are extracted into an organic solvent such as ethyl acetate or chloroform. Compounds 48 and 49 can be separated and/or purified by any suitable technique, or combination of techniques, such as chromatography or trituration.

The 4-nitrobenzenesulfonate compound 37 can be prepared according to an exemplary synthetic route according to Scheme 6.

Referring to Scheme 6, 1,4-dioxaspiro[4.5]decan-8-ol 37-1 is first treated with a base, such as sodium hydride or potassium tert-butoxide, in a suitable solvent, and then with RX -LG, to form compounds 37 2 , where LG is a suitable leaving group, such as chloride, bromide, iodide, tosylate or mesylate. Suitable solvents include, but are not limited to, aprotic solvents, such as THF, DMF, acetonitrile, dioxane, ether, or a combination thereof. After the reaction has gone substantially to completion, aqueous acid such as HCl is added to quench the reaction to form compound 37-3.

Compound 37-3 is then treated with a reducing agent to form Compound 37-4. Compound 37-4 may be substantially one isomer or, alternatively, Compound 37-4 may be a mixture of cis and trans isomers, and ^{in In some embodiments, compound 37-4 comprises a 2:1 mixture of} cis:trans isomers. ^{The reducing agent} can be any agent that can reduce the carbonyl moiety to an alcohol moiety. Suitable reducing agents include, but are not limited to lithium aluminum hydride, diisobutylaluminum hydride, borane-THF, or a borohydride reagent such as sodium borohydride. Suitable solvents to facilitate the reaction include, but are not limited to THF, ether, or a combination thereof.

Compound 37-4 is treated with 4-nitrobenzenesulfonyl (nosyl) chloride in the presence of base to form compound 37. The base can be any suitable base that facilitates the reaction and can be an organic base, such as trimethylamine, 1, 4-diazabicyclo[2.2.2]octane (DABCO), pyridine or Hunig's base; or an inorganic base, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction can proceed in a suitable solvent, typically an aprotic solvent, such as pyridine, THF, or a chlorinated solvent, such as dichloromethane or chloroform. Compound 37 can be substantially one isomer or, alternatively, Compound 37 can be a mixture of isomers. The isomer ratio can be modified by a suitable technique, such as ^{chromatography or trituration. In some embodiments, the isomer ratio is changed to about 8:1} cis ^to trans by trituration.

Alternatively, compound 40 can be prepared according to an exemplary synthetic route according to Scheme 7.

Referring to Scheme 7, compound 36 is reacted with compound 50 to form compound 52. Compound 50 comprises a desired ring, such as a cyclobutyl, cyclopentyl, or cyclohexyl ring, a suitable leaving group LG, and a protected carbonyl moiety, such as as an acetal or a ketal. A cyclic ketal moiety is shown in the example above. Suitable leaving groups include any group that acts as a leaving group to facilitate ring addition to compound 36, and include, but are not limited to, halogens, typically bromo, chloro, or iodo, and tosylate or mesylate groups. Compound 36 is reacted with compound 50 in a suitable solvent and typically in the presence of base. Suitable solvents include any solvent that facilitates the reaction such as aprotic solvents. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents, such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that facilitates the reactions such as a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate or cesium carbonate. The reaction can proceed at room temperature or, alternatively, the reaction mixture can be heated such as at a temperature within the range of temperatures greater than room temperature to the boiling point of the selected solvent, such as at 50 °C, 100 °C C or greater, as required. Compound 52 is then isolated from the reaction mixture and purified, if required, by a suitable technique such as column chromatography.

Compound 52 is then reacted with a suitable reagent 54 to form compound 40. Reagent 54 can be any suitable reagent to remove the protecting group and/or form the carbonyl moiety. In the exemplary synthesis shown in Scheme 5, the protecting group is a cyclic ketal, and suitable reagents include, but are not limited to, pyridinium tosylate (PPTS), para-toluenesulfonic acid, hydrochloric acid, or acetic acid. The reaction is carried out in a suitable solvent or solvent mixture to facilitate the reaction, such as acetone, THF, acetic acid, water, or a combination thereof. The reaction can proceed at room temperature or, alternatively, the reaction mixture can be heated such as at a temperature within the range of temperatures greater than room temperature to the boiling point of the selected solvent, such as at 50 °C, 100 °C C or greater, as required. Compound 40 is then isolated from the reaction mixture and purified, if required, by a suitable technique such as column chromatography.

An exemplary 2nd step reaction sequence according to Scheme 8 is provided below.

Compound 48 is reacted with a suitable reducing agent 56, to reduce the nitro moiety to an amine. In certain embodiments where the desired product compound comprises a hydroxyl moiety, compound 44 may be used in place of compound 48. Suitable reducing agents include, but are not limited to: hydrogen gas in the presence of a catalyst such as a palladium catalyst ; a borohydride such as sodium borohydride, optionally in the presence of a catalyst such as a nickel catalyst; metallic zinc in acetic acid; or iron powder in water or water and acid. In certain embodiments, hydrogen gas is used, in the presence of a palladium-on-carbon catalyst, and in a suitable solvent, such as ethyl acetate or methanol. In some embodiments, a combination of reducing agents and/or techniques is used. For example, the reduction can initially carried out using a first method that comprises a first reducing agent and/or technique, but results in a mixture of products. The first method can be repeated and/or a second method can be performed, comprising a second reducing agent and/or technique. Once the reaction is complete, as indicated by an analytical technique such as LC-MS, TLC, or HPLC, product compound 58 is isolated and purified if necessary.

Compound 58 is reacted with a carboxylic acid 60 to form amide 62. Carboxylic acid 60 is activated by any suitable method and then reacted with the amine functional group of compound 58. Suitable activation methods include, but are not limited to a: form the acid chloride by treatment with thionyl chloride; treatment with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and a base such as diisopropylethylamine (DIPEA); by treatment with carbonyldiimidazole (CDI); or treatment with a carbodiimide, such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

Compound 62 is then coupled with compound 64 to form compound 66 using any suitable coupling reaction to form a bond between two rings. A boronic ester coupling is shown in the above example, in which the leaving group LG in compound 62 is typically bromo or iodo. Other suitable coupling functional groups include trialkyl tin or boronic acids. The coupling reaction typically proceeds in the presence of a suitable catalyst. For a boronic ester or boronic acid coupling, the catalyst is usually a palladium catalyst, such as PdCl ² (dppf) ² , Pd[P(Ph) ₃ ]2Cl2, palladium acetate and triphenylphosphine, or

tetrakis(triphenylphosphine)palladium(0). The reaction is carried out in the presence of a base, such as sodium, potassium or cesium carbonate, and is carried out in a suitable solvent or solvent mixture, such as dioxane, dioxane/water or DME/ethanol/water. The reaction can be heated to a suitable temperature such as 50°C to 125°C, typically about 100°C, and/or stirred for a suitable period of time, such as 1 hour to 3 days, 6 hours to 24 hours or from 12 hours to 18 hours, to allow the reaction to proceed to completion. Compound 66 is then isolated from the reaction mixture and purified by a suitable technique.

Certain embodiments may comprise a phosphate moiety. Scheme 9 provides an exemplary summary of certain such embodiments.

Compound 68 is reacted with compound 70 to form compound 72. Compound 70 comprises the desired Ry moieties and a suitable leaving group, LG. Typical Ry moieties include, but are not limited to, aliphatics such as alkyl, typically methyl, ethyl, propyl, isopropyl, or t-butyl; aryl; heteroaliphatic; or heterocyclic. The two Ry moieties may be the same or different. Suitable leaving groups include, but are not limited to halogens, typically bromo, chloro or iodo, and tosylate or mesylate groups. Compound 68 is reacted with compound 70 in a suitable solvent and typically in the presence of base. Suitable solvents include any solvent that facilitates the reaction such as aprotic solvents. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents, such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that facilitates the reactions such as a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate or cesium carbonate. The reaction can proceed at room temperature or, alternatively, the reaction mixture can be heated such as to a temperature within the range of temperatures greater than room temperature. to the boiling point of the selected solvent, such as at 50°C, 100°C or higher, as required. Compound 72 is then isolated from the reaction mixture and purified if necessary.

Compound 72 is then reacted with compound 74 to form compound 76. Compound 74 can be any suitable compound to form the acid moieties in compound 76. Compound 74 can be an acidic reagent, such as trifluoroacetic acid, hydrochloric acid, or hydrobromic, or it can be a basic reagent, such as sodium hydroxide, lithium hydroxide or potassium hydroxide. Suitable solvents include, but are not limited to, chlorinated solvents, such as dichloromethane and chloroform, alcohols, such as methanol and ethanol, water, or combinations thereof. The reaction can proceed at room temperature or, alternatively, the reaction mixture can be heated such as at a temperature within the range of temperatures greater than room temperature to the boiling point of the selected solvent, such as at 50 °C, 100 °C C or greater, as required. The reaction mixture can also be cooled, for example, below 20°C, below 10°C, below 0°C or less. After the reaction is complete, as indicated by an analytical technique such as LC-MS, TLC or HPLC, product compound 76 is isolated and purified if necessary, by a suitable technique such as shaking or sonication, in a suitable solvent or solvent system. Suitable solvents or solvent systems include, but are not limited to, acetone/water, acetone, diethyl ether, or alcohol/water.

Compound 76 is then reacted with compound 78 to form salt compound 80. Compound 78 can be any compound that provides a suitable counterion (CI) for salt compound 80, such as calcium hydroxide, sodium hydroxide , potassium hydroxide, lithium hydroxide, ammonia, trimethylamine, tris(hydroxymethyl)aminomethane, or an amino acid such as lysine or arginine. One skilled in the art will appreciate that if the CI counterion has a single positive charge, such as in Na+, K+, Li+, or NH ⁴ +, then compound 80 will comprise two CI ions, whereas if the CI counterion has two positive charges , as in Cl ₂ + , compound 80 will comprise a CI ion.

C. Combinations of Therapeutic Agents

The amide compounds of the present invention can be used alone, in combination with each other, or as an adjunct to or in combination with other established therapies. In another aspect, the compounds of the present invention may be used in combination with other therapeutic agents useful for the disorder or condition being treated. These compounds can be administered simultaneously, sequentially in any order, by the same route of administration or by a different route.

In some embodiments, the second therapeutic agent is an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase-C agonist, an intestinal secretagogue, an antiviral, anticancer, antifungal, or a combination of the same. The anti-inflammatory agent can be a steroid or a non-steroidal anti-inflammatory agent. In certain embodiments, the non-steroidal anti-inflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, antilymphocyte globulin, antithymocyte globulin, an anti-T cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

In some embodiments, the present compounds can be used with other anticancer or cytotoxic agents. Various classes of anticancer and antineoplastic compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, hormones and hormone antagonists, and hypomethylating agents, for example DNMT inhibitors, such as azacitidine and decitabine. Examples of alkylating agents include, without limitation, mechlorotamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, alkyl sulfonates (eg, busulfan), and carmustine. Exemplary antimetabolites include, by way of example and not limitation, folic acid analog methotrexate; fluorouracil pyrimidine analog, cytosine arabinoside; purine analogues mercaptopurine, thioguanine and azathioprine. Exemplary vinca alkyloids include, by way of example and not limitation, vinblastine, vincristine, paclitaxel, and colchicine. Examples of antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. An exemplary enzyme effective as an antineoplastic agent includes L-asparaginase. Exemplary coordination compounds include, by way of example and not limitation, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, by way of example and not limitation, adrenocorticosteroids prednisone and dexamethasone; aromatase inhibitors amino glutethimide, formestane and anastrozole; progestin compounds hydroxyprogesterone caproate, medroxyprogesterone; and the anti-estrogen compound tamoxifen.

These and other useful anticancer compounds are described in the Merck Index, 13th Ed. (O'Neil M.J. et al., ed.) Merck Publishing Group (2001) and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Edition, Brunton L.L. ed., Chapters 60-63, McGraw Hill, (2011).

Among the CTLA 4 antibodies that can be used in combination with currently described inhibitors is ipilimumab, marketed as YERVOY® by Bristol-Myers Squibb.

Other combination chemotherapeutic agents include immuno-oncology agents such as checkpoint pathway inhibitors, for example, PD-1 inhibitors, such as nivolumab and lambrolizumab, and PD-L1 inhibitors, such as pembrolizumab, MEDI-4736, and MPDL3280N RG7446. Additional checkpoint inhibitors for combination with the compounds described herein include Anti-LAG-3 agents, such as BMS-986016 (MDX-1408).

Other chemotherapeutic agents to combine with the inhibitors described herein include anti-SLAMF7 agents, such as the humanized monoclonal antibody elotuzumab (BMS-901608), anti-KIR agents, such as the anti-KIR monoclonal antibody lirilumab (BMS-986015) , and anti-CD137 agents, such as the fully human monoclonal antibody urelumab (BMS-663513).

Additional antiproliferative compounds useful in combination with the compounds of the present invention include, by way of example and not limitation, antibodies directed against growth factor receptors (eg, anti-Her2); and cytokines such as interferon-a and interferon-Y, interleukin-2, and GM-CSF.

Additional chemotherapeutic agents useful in combination with the present amide compounds include proteasome inhibitors, such as bortezomib, carfilzomib, marizomib, and the like.

Examples of kinase inhibitors that are useful in combination with the compounds described herein, particularly in the treatment of malignancies, include Btk inhibitors such as ibrutinib, CDK inhibitors such as palbociclib, EGFR inhibitors such as afatinib, erlotinib , gefitinib, lapatinib, osimertinib and vandetinib, Mek inhibitors such as trametinib, Raf inhibitors such as dabrafenib, sorafenib and vemurafenib, VEGFR inhibitors such as axitinib, lenvatinib, nintedanib, pazopanib, BCR-Abl inhibitors such such as bosutinib, dasatinib, imatinib, and nilotinib, Syk inhibitors such as fostamatinib, and JAK inhibitors such as ruxolitinib. In other embodiments, the second therapeutic agent can be selected from any of the following:

Analgesics - morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, dipipanone;

antibiotics-aminoglycosides (eg, amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (eg, ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (eg, cefadroxil , cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, and cefobiprol), glycopeptides (eg, teicoplan inna , vancomycin, and telavancin), lincosamides (eg, clindamycin, and incomysin), lipopeptides (eg, daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, and spectinomycin), monobactams (p eg, aztreonam), nitrofurans (eg, furazolidone and nitrofurantoin), penicillins (eg, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G , penicillin V, piperacillin, temocillin and ticarcillin), combinations of penicillins (eg. g., amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, and ticarcillin/clavulanate), polypeptides (eg, bacitracin, colistin, and polymyxin B), quinolones (eg, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (eg, mafenide, sulfonamidochrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethoxazole, sulfasalazine, sulfisoxazole, trimethoprim and trimethoprim-sulfamethoxazole ), tetracyclines (eg, demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), antimycobacterial compounds (eg, clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin , rifapentin, and streptomycin) and others, such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimicin, quinuprisin/dalfopristin, rifaximin, thiamphenicol, tigecycline, and thymidazole;

antibodies - anti-TNF-a antibodies, eg infliximab (Remicade™), adalimumab, golimumab, certolizumab; anti-B cell antibodies, for example rituximab; anti-IL-6 antibodies, for example tocilizumab; anti-IL-1 antibodies, for example anakinra; anti-PD-1 and/or anti-PD-L1 antibodies, for example nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab;

anticoagulants - warfarin (Coumadin™), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin

anti-inflammatory agents - steroids, e.g. eg, budesonide, non-steroidal anti-inflammatory agents, e.g. eg, aminosalicylates (eg, sulfasalazine, mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors, such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin;

immunosuppressants - mercaptopurine, corticosteroids such as dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisolone, alkylating agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus, inosine monophosphate dehydrogenase (IMPDH) inhibitors, such as mycophenolate , mycophenolate mofetil, and azathioprine, and agents designed to suppress cellular immunity while leaving the recipient's humoral immune response intact, including various antibodies (eg, antilymphocyte globulin (ALG), antithymocyte globulin (ATG), anti-cell monoclonal antibodies). T(OKT3)) and irradiation. Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the brand name Azasan; Mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the brand name Purinethol; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; Methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the brand name Rapamune; tacrolimus is currently available from Fujisawa under the brand name Prograf; Cyclosporine is currently available from Novartis under the brand name Sandimmune and Abbott under the brand name Gengraf; IMPDH inhibitors, such as mycophenolate mofetil and mycophenolic acid, are currently available from Roche under the brand name Cellcept and Novartis under the brand name Myfortic; Azathioprine is currently available from Glaxo Smith Kline under the brand name Imuran; and the antibodies are currently available from Ortho Biotech under the brand name Orthoclone, Novartis under the brand name Simulect (basiliximab) and Roche under the brand name Zenapax (daclizumab); and

guanylate cyclase-C receptor agonists or intestinal secretagogues - eg linaclotide, sold under the name Linzess.

These various agents can be used according to their standard or common dosages, as specified in the prescribing information accompanying the commercially available forms of the drugs (see also the prescribing information in the 2006 edition of The Physician's Desk Reference). ).

D. Compositions Comprising Amide Compounds

The described amide compounds can be used alone, in any combination, and in combination with, or as an adjunct to, at least one second therapeutic agent, and furthermore the amide compounds and the at least one second therapeutic agent can be used in combination. with any suitable additive useful to form compositions for administration to a subject. Additives can be included in pharmaceutical compositions for a variety of purposes such as diluting a composition for administration to a subject, facilitating processing of the formulation, providing advantageous material properties to the formulation, facilitating dispersion from a delivery device, stabilizing the formulation (eg, antioxidants or buffers), to provide a pleasant or palatable flavor or consistency to the formulation, or the like. Typical additives include, by way of example and without limitation: pharmaceutically acceptable excipients; pharmaceutically acceptable carriers; and/or adjuvants such as mono-, di-, and polysaccharides, sugar alcohols, and other polyols, such as lactose, glucose, raffinose, melecitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants, such as sorbitols, diphosphatidylcholine, and lecithin; consistency conferring agents; buffers, such as phosphate and citrate buffers; anti-stick agents such as magnesium stearate; binders such as saccharides (including disaccharides, such as sucrose and lactose), polysaccharides (such as starches, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols), coatings (such as cellulose ethers, including hydroxypropylmethylcellulose, shellac, corn protein zein, and gelatin); release aids (such as enteric coatings); disintegrants (such as crospovidone, cross-linked sodium carboxymethylcellulose, and sodium starch glycolate); fillers (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavors and sweeteners (such as mint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla lubricants (such as minerals, exemplified by talc or silica, greases, exemplified by vegetable stearin, magnesium stearate or stearic acid); preservatives (such as antioxidants exemplified by vitamin A, vitamin E, vitamin C, retinyl and selenium palmitate, amino acids, exemplified by cysteine and methionine, citric acid and sodium citrate, parabens, exemplified by methylparaben and propylparaben); dyes; compression aids; emulsifying agents; encapsulation agents; gums; granulating agents; and combinations thereof.

III. Methods of Use

A. Diseases/Disorders

The described amide compounds, as well as their combinations and/or compositions, can be used to ameliorate, treat or prevent a variety of diseases and/or disorders. In particular embodiments, the amide compound, combinations of amide compounds, or compositions thereof, may be useful for treating conditions in which inhibition of an interleukin-1 receptor associated kinase (IRAK) pathway is therapeutically useful. . In some embodiments, the compounds directly inhibit an IRAK protein, such as IRAK1, IRAK ₂ , IRAK3, IRAK4, or a combination thereof. In certain embodiments, the described amide compounds are useful for treating, preventing, or ameliorating autoimmune diseases, inflammatory disorders, cardiovascular diseases, nervous disorders, neurodegenerative disorders, allergic disorders, asthma, pancreatitis, multiple organ failure, renal diseases, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, graft rejection, lung lesions, respiratory diseases, ischemic conditions, and bacterial and viral infections.

In some embodiments, the amide compound, combinations of amide compounds. or compositions thereof. may be used to treat or prevent allergic diseases, amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, or asthma.

The amide compound, combinations of amide compounds, or compositions thereof, may also be useful for ameliorating, treating, or preventing disorders of immune regulation related to bone marrow or organ transplant rejection, or graft disease. against host. Examples of disorders of inflammatory and immune regulation that can be treated with the present compounds include, but are not limited to, organ or tissue transplantation, graft-versus-host diseases caused by transplantation, autoimmune syndromes including rheumatoid arthritis, lupus erythematosus systemic, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, Atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, mixture flat, pénfigigo, blistering penfigoid, ampouple epidermolysis, urticaria, angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, conjunctivitis vernal vernal , associated uveitis Behcet's disease, keratitis, herpetic keratitis, conical cornea, epithelial dystrophy of the cornea, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late-onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture syndrome , hemolytic uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, thrombocytopenic purpura idiopathic, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteries clerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposis, eosinophilic fasciitis, gum lesions, periodontium, alveolar bone, dental bone substance, glomerulonephritis, male pattern alopecia or senile alopecia al prevent hair removal or facilitate hair germination and/or promote hair generation and growth, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, ischemia-reperfusion injury to organs that occurs after preservation, transplantation or Ischemic disease, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure, pulmonary oxygen or drug toxins, lung cancer, emphysema, cataract, siderosis, retinitis pigmentosa, senile macular degeneration , vitreous healing, corneal alkali burn, dermatitis erythema multiforme, linear IgA bullous dermatitis and cementum dermatitis, gingivitis, periodontitis, septicemia, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, carcinoma metastasis and hypobaropathy, disease caused due to histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatic resection, acute hepatic necrosis, necrosis caused by toxin, viral hepatitis, shock or anoxia, B virus hepatitis, non-hepatitis N non-B, cirrhosis, alcoholic liver disease including alcoholic cirrhosis, nonalcoholic steatohepatitis (NASH), liver failure, fulminant liver failure, late-onset liver failure, “acute on chronic” liver failure, increased chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma, or chronic bacterial infection.

In certain embodiments, the present compounds are useful for treating nerve pain, including neuropathic pain and pain induced by inflammation.

In certain embodiments, the amide compound, combinations of amide compounds, or compositions thereof, are useful for treating and/or preventing rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, sclerosis systemic, multiple sclerosis, psoriasis, in particular pustular psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Cronh's disease and ulcerative colitis), hyperimmunoglobulinemia d and periodic fever syndrome, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gout flare-ups, pseudogout, sapho syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (Il-1 receptor antagonist deficiency) , Alzheimer's disease, Parkinson's disease.

Proliferative diseases that can be treated with the amide compound, combinations of amide compounds, or compositions thereof, include benign or malignant tumors, solid tumors, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric, ovarian, colon, rectal, prostate, pancreas, lung, vagina, cervix, testicles, genitourinary tract, esophagus, larynx, skin, bone or thyroid tumors, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially carcinoma of colon or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostatic hyperplasia, a neoplasm, a neoplasm of an epithelial nature, adenoma, adenocarcinoma, keratoacanthoma, squamous cell carcinoma, large cell carcinoma, non-small cell lung carcinoma , lymphomas, Hodgkin and non-Hodgkin, a breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, disorders caused by IL-1, a disorder caused by MyD88 (such as diffuse large B-cell lymphoma ABC (DLBCL ), Waldenstrom macroglobulinemia, Hodgkin lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia), smoldering or indolent multiple myeloma, or hematologic malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, ABC DLBCL, lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, macroglobulinemia of Waldenstrom (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the compounds described herein are useful in the treatment of drug-resistant malignancies, such as those resistant to JAK inhibitors, ibrutinib-resistant malignancies, including ibrutinib-resistant hematologic malignancies, such as ibrutinib-resistant CLL. and Waldenstrom's macroglobulinemia resistant to ibrutinib.

Examples of allergic disorders that can be treated using the amide compound, combinations of amide compounds, or compositions thereof, include, but are not limited to, asthma (eg, atopic asthma, allergic asthma, atopic bronchial asthma mediated by IgE, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological changes, essential asthma of unknown or unknown cause, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, extrinsic asthma caused by environmental factors, cold air-induced asthma, occupational asthma, infectious asthma caused by or associated with a bacterial, fungal, protozoal, or viral infection, incipient asthma, wheezing infant syndrome, bronchiolitis, variant asthma with cough, or induced asthma from drugs), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, purulent or nonpurulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoid sinusitis.

As another example, rheumatoid arthritis (RA) typically results in swelling, pain, loss of motion, and tenderness in target joints throughout the body. RA is characterized by chronic inflammation of the synovial membrane densely populated with lymphocytes. The synovial membrane, which is usually one cell layer thick, becomes intensely cellular and takes on a form similar to lymphoid tissue, including dendritic cells, T cells, NK band cells, macrophages, and plasma cell clusters. This process, as well as a plethora of immunopathological mechanisms, including the formation of antigen-immunoglobulin complexes, ultimately results in the destruction of joint integrity, resulting in deformity, permanent loss of function, and/or bone erosion at the joint. joint or near it. The amide compound, combinations of amide compounds, or compositions thereof, can be used to treat, ameliorate, or prevent any, several, or all of these RA symptoms. Therefore, in the context of RA, compounds are considered to provide therapeutic benefit when a reduction or amelioration of any of the symptoms commonly associated with RA is achieved, regardless of whether the treatment results in concomitant treatment of RA. underlying RA and/or a reduction in the amount of circulating rheumatoid factor ("RF").

The American College of Rheumatology (ACR) has developed criteria to define clinical improvement and remission in RA. Once this parameter is reached, the ACR20 (ACR criteria for a 20% clinical improvement), requires a 20% improvement in the count of tender and swollen joints, as well as a 20% improvement in 3 of the following 5 parameters: patient global assessment, physician global assessment, patient assessment, patient assessment of pain, degree of disability, and acute phase reactant level.

These criteria have been expanded for a 50% and 70% improvement in ACR50 and ACR70, respectively. Other criteria include the Paulu criteria and radiographic progression (eg, Sharp score).

In some embodiments, therapeutic benefit in patients suffering from RA is achieved when the patient has an ACR20. In specific embodiments, ACR improvements of ACRC50 or even ACR70 can be achieved.

B. Formulations and Administration

Pharmaceutical compositions comprising one or more active amide compounds of the invention may be manufactured by mixing, dissolving, granulating, drageeizing, levigating, emulsifying, encapsulating, entrapment, or freeze-drying processes. The compositions may be formulated using one or more physiologically acceptable excipients, diluents, carriers, adjuvants or auxiliaries to provide pharmaceutically usable preparations.

^{The active compound(s) can be formulated into the pharmaceutical compositions} per se, ^{or in pharmaceutically acceptable hydrate, solvate, N-oxide or salt form} . Typically, salts of this type are more soluble in aqueous solutions than the corresponding free acids and bases, but salts that have a lower solubility than the corresponding free acids and bases can also be formed.

Pharmaceutical compositions of the invention may take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, such as i.v. or i.p., transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation.

For topical administration, the active compound(s), hydrate, solvate, N-oxide, or pharmaceutically acceptable salt may be formulated as solutions, gels, ointments, creams, suspensions, etc., as known in the art.

Systemic formulations include those designed for administration by injection, e.g. eg, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles. The compositions may also contain formulatory agents, such as suspending, stabilizing and/or dispersing agents. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or multi-dose containers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including, but not limited to, sterile, pyrogen-free water, buffer, dextrose solution, etc., prior to use. To this end, the active compound(s) can be dried by any technique known in the art, such as lyophilization, and reconstituted before use.

For transmucosal administration, penetrants appropriate for the barrier to be traversed are used in the formulation. Penetrants of this type are known in the art.

For oral administration, the pharmaceutical compositions may take the form of, for example, pills, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as: binding agents (eg pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose ); fillers (eg, lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (eg, magnesium stearate, talc, or silica); disintegrants (eg, potato starch or sodium starch glycolate); and/or wetting agents (eg, sodium lauryl sulfate). Tablets can be coated by methods well known in the art, for example, with sugars, films or enteric coatings.

Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations of this type can be prepared by conventional means with pharmaceutically acceptable additives such as: suspending agents (eg, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (eg, lecithin or acacia); non-aqueous vehicles (eg, almond oil, oily esters, ethyl alcohol, cremophore™, or fractionated vegetable oils); and preservatives (eg, methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavors, colors and sweeteners, as appropriate.

Preparations for oral administration can be suitably formulated to give a controlled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of conventionally formulated tablets or lozenges.

For rectal and vaginal routes of administration, the active compound(s) may be formulated as solutions (for retention enemas), suppositories, or ointments containing conventional suppository bases, such as cocoa butter or other glycerides.

For nasal administration or administration by inhalation or insufflation, the active compound(s), hydrate, solvate, N-oxide, pharmaceutically acceptable salt may conveniently be administered as an aerosol spray from pressurized packets or a nebulizer with the use of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator (for example, gelatin composite capsules and cartridges) may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

A specific example of an aqueous suspension formulation, suitable for nasal administration, using commercially available nasal spray devices includes the following ingredients: active compound (0.5-20 mg/ml); benzalkonium chloride (0.1-0.2 mg/ml); polysorbate 80 (TWEEN® 80; 0.55 mg/ml); sodium carboxymethylcellulose or microcrystalline cellulose (1-15 mg/ml); phenylethanol (14mg/ml); and dextrose (2050 mg/ml). The pH of the final suspension can be adjusted in the range of about pH 5 to pH 7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension, suitable for administration of the compounds by inhalation, contains 20 mg/ml of the amide compound(s), 1% (v/v) polysorbate 80 (TWEEN® 80), 50 mM citrate and /or 0.9% sodium chloride.

For ocular administration, the active amide compound(s) may be formulated as a solution, emulsion, suspension, etc., suitable for administration to the eye. A variety of vehicles suitable for delivering compounds to the eye are known in the art. Specific, non-limiting examples are described in US Pat. US Nos. 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851.

For prolonged administration, the active amide compound(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient may be formulated with suitable polymeric or hydrophobic materials (eg as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, eg. g., as a sparingly soluble salt. Alternatively, transdermal delivery systems manufactured as an adhesive disc or patch that slowly release the active compound(s) for percutaneous absorption may be used. To this end, permeation enhancers may be used to facilitate transdermal penetration of the active compound(s). Suitable transdermal patches are described, for example, in US Pat. US Nos. 5,407,713; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110 and 4,921,475.

Alternatively, other pharmaceutical delivery systems may be employed. Liposomes and emulsions are well known examples of delivery vehicles that can be used to deliver the active compound(s). Certain organic solvents such as dimethyl sulfoxide (DMSO) can also be used, although usually at the cost of increased toxicity.

The pharmaceutical compositions may, if desired, be presented in a container or dispensing device that may contain one or more unit dosage forms containing the active compound(s). The pack may comprise, for example, metal or plastic foil such as a blister pack. The package or dispensing device may be accompanied by instructions for administration.

C. Dosages

The amide compound, or combinations of amide compounds, will generally be used in an amount effective to achieve the desired result, for example in an amount effective to treat, prevent, or ameliorate a particular condition. The amide compound(s), or compositions thereof, may be administered therapeutically to achieve therapeutic benefit, or prophylactically to achieve prophylactic benefit. Therapeutic benefit means the eradication or amelioration of the underlying disorder being treated and/or the eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in sensation or condition, despite that the patient may still be affected with the underlying disorder. For example, administration of a compound to a patient suffering from an allergy provides therapeutic benefit not only when the underlying allergic response is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of symptoms associated with the allergy. allergy after allergen exposure. As another example, therapeutic benefit in the context of asthma includes an improvement in breathing after the onset of an asthma attack or a reduction in the frequency or severity of asthma episodes. The benefit Therapeutic also includes stopping or slowing the progression of the disease, regardless of whether improvement is achieved.

As is known to those skilled in the art, the preferred dosage of amide compounds may depend on a number of factors, including the age, weight, general health, and severity of the condition of the patient or subject being treated. It may also be necessary to tailor the dose to the sex of the individual, and/or the lung capacity of the individual, when administered by inhalation. Dosage can also be tailored for people who have more than one condition or those who have additional conditions that affect lung capacity and the ability to breathe normally, for example, emphysema, bronchitis, pneumonia, and respiratory infections. The dosage and frequency of administration of the amide compound(s) or compositions thereof will also depend on whether the amide compound(s) are formulated for the treatment of acute episodes of a condition, or for the prophylactic treatment of a disorder. . One of ordinary skill in the art will be able to determine the optimum dosage for a particular individual.

For prophylactic administration, the amide compound, combinations of amide compounds, or compositions thereof, can be administered to a patient or subject at risk of developing one of the previously described conditions. For example, if it is not known whether a patient or subject is allergic to a particular drug, the amide compound, combinations of amide compounds, or compositions thereof, may be administered prior to drug administration to prevent or ameliorate a allergic response to the drug. Alternatively, prophylactic administration may be used to prevent or ameliorate the onset of symptoms in a patient diagnosed with the underlying disorder. For example, one or more amide compounds, or a composition thereof, can be administered to an allergy sufferer prior to the expected exposure to the allergen. An amide compound, combinations of amide compounds, or compositions thereof, may also be administered prophylactically to healthy individuals, who are repeatedly exposed to agents known for one of the diseases described above to prevent the onset of the disorder. For example, an amide compound, combinations of amide compounds, or compositions thereof, can be administered to a healthy individual, who is repeatedly exposed to an allergen known to induce allergies, such as latex, in an effort to to prevent the individual from developing an allergy. Alternatively, an amide compound, combinations of amide compounds, or compositions thereof, may be administered to a patient suffering from asthma prior to engaging in activities that trigger asthma attacks, in order to lessen the severity of an asthmatic episode or to avoid it for good. complete.

^{Effective dosages can be initially estimated from} in vitro assays. ^{For example, an initial dosage for use in subjects may be formulated} to achieve a concentration of active compound in ^{circulating blood or serum that is at or above an IC50 or EC50 of the particular compound as measured in an} in vitro assay. ^Dosages can be calculated to achieve circulating blood or serum concentrations of this type, taking into account the bioavailability of the particular compound. Fingl & Woodbury, "General Principles," In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, Pergamon Press, and the references cited therein, provide additional guidance on effective dosages.

In some embodiments, the disclosed compounds have an EC ⁵⁰ of greater than 0 to 20 µM, such as greater than 0 to 10 µM, greater than 0 to 5 µM, greater than 0 to 1 µM, greater than 0 to 0.5 μM, greater than 0 to 0.1 μM, or greater than 0 to 0.05 μM.

^{Starting dosages can also be estimated from} in vivo data ^{such as animal models.} Animal ^models useful for testing the efficacy of compounds in treating or preventing the various diseases described above are well known in the art. Suitable animal models of hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50(21Suµl):6-9, discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol.

107(6): 1025-1033. Suitable animal models of allergic rhinitis are described in Szelenyi et al., (2000), Arzneimittelforschung 50(11): 1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy 24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1): 1-7. Persons of ordinary skill in the art can adapt such information to determine suitable dosages for human administration.

Dosage amounts of the amide compounds described will typically be in the range of about greater than 0 mg/kg/day, such as 0.0001 mg/kg/day or 0.001 mg/kg/day or 0.01 mg/ kg/day, to at least less than about 100 mg/kg/day. More typically, the dosage (or effective amount) can range from about 0.0025 mg/kg to about 1 mg/kg administered at least once daily, such as from 0.01 mg/kg to about 0.5 mg/ kg or from about 0.05 mg/kg to about 0.15 mg/kg. Total daily dosage typically ranges from about 0.1 mg/kg to about 5 mg/kg or about 20 mg/kg per day, such as from 0.5 mg/kg to about 10 mg/kg per day or from about 0 0.7 mg/kg per day to approximately 2.5 mg/kg/day. Dosage amounts can be higher or lower, depending, among other factors, on the activity of the amide compound, its bioavailability, the mode of administration, and various factors discussed above.

The dosage amount and dosage interval can be adjusted for individuals to provide plasma levels of the amide compound that are sufficient to maintain therapeutic or prophylactic effect. For example, the compounds can be administered once a day, multiple times a day, once a week, multiple times a week (eg, every other day), once a month, multiple times a month, or once a year, depending, among other things, the mode of administration, the specific indication being treated and the criteria of the prescribing physician. Those of ordinary skill in the art will be able to optimize effective local dosages without undue experimentation.

Compositions comprising one or more of the amide compounds typically described comprise from greater than 0 to 99% of the amide compound(s), and/or other therapeutic agent by total weight percent. More typically, compositions comprising one or more of the described amide compounds comprise from about 1 to about 20 percent by total weight of the amide compound and other therapeutic agent, and from about 80 to about 99 percent by weight of a pharmaceutically acceptable additive. Preferably, the amide compound, combinations of amide compounds, or compositions thereof will provide therapeutic or prophylactic benefit without causing substantial toxicity. The toxicity of the amide compound can be determined using standard pharmaceutical procedures. The dose relationship between the toxic and therapeutic (or prophylactic) effect is the therapeutic index. Amide compounds that exhibit high therapeutic indices are preferred.

IV. examples

The following section provides examples and reference examples. Any compounds that are outside the scope of the claims are included for reference purposes only.

Example 1

6-bromo-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (I-1)

A CH ² G ² (40 mL) solution of 6-bromopicolinic acid (2.02 g, 10 mmol), 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-amine dihydrochloride ( 2.52 g, 10.2 mmol), HATU (4.56 g, 12 mmol) and DIPEA (5.4 mL, 31 mmol) was stirred at room temperature for 15 hours. The reaction was complete as monitored by LC-MS. To the reaction mixture, saturated aqueous NaHCO ₃ solution (ca. 100 mL) was added, mixed well, two layers were separated; the aqueous layer was extracted with CH ² G ² (20 ml x 2). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered, the solvent removed in vacuo. The crude product was further treated with saturated aqueous NaHCO ₃ solution (ca. 80 mL), mixed well, and the precipitate collected by filtration, washing with H ² O (ca. 10 mL x 5), dried further. to empty. The compound 6-bromo-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide was obtained as a light beige solid: 2.70 g (75% of performance); ¹ H NMR (300 MHz, ^{chloroform-d) 13.09 (s, 1H), 8.84 (ddd,} j ^{= 4.9, 1.8, 1.0 Hz, 1H), 8.36 (s, 1H), 8.21 (dd,} j ^{= 7.5, 1.0 Hz, 1H), 8.04 (ddd,} j ^{= 8.1, 1.1, 1.1 Hz, 1H), 7.77 (ddd, j = 8.1, 7.5, 1.8 Hz, partially overlapped, 1H), 7.78 - 7.73 (m, partially} overlapped, 1H), 7.65 (dd, j = 7.9, 1 .0 Hz, 1H), 7.26-7.22 (m, partially overlapped with CHCta, 1H), 3.98 (s, 3H); LRMS ^(M+H) m/z ^{358.45, 360.33.}

Example 2

N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-2)

0.1 mmol scale, with (5-fluoropyridin-3-yl)boronic acid, 2.6 mg, 6.8% yield. NMR (300 MHz, DMSO-ofe) ^{12.53 (s, 1H), 9.71 (d,} J ^{=2.0 Hz, 1H), 8.82-8.80 (m, 2H), 8, 69 (ddd,} J ^{= 8.0, 1.7, 1.7 Hz, 1 H), 8.55 (s, 1 H), 8.37 (dd,} J ^{= 7.2, 1.7 Hz, 1H), 8.25 - 8.17 (m, 2H), 8.06 (d,} J ^{= 8.0 Hz, 1H), 7.95 (ddd,} J ^{= 7.9, 7.9, 1, 7 Hz, 1H), 7.72 (dd,} J ^{= 7.9, 4.8 Hz, 1H), 7.45 (ddd,} J ^{= 7.3, 5.0, 1.1 Hz, 1H), 4.00 (s, 3H); LRMS (M+H)}

Example 3

5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-3)

A 1,4-dioxane (3 mL) solution of 6-bromo-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (71.6 mg, 0 0.2 mmol), (5-fluoropyridin-3-yl)boronic acid (42.3 mg, 0.3 mmol), Pd(PPh3)4 (23.1 mg, 0.02 mmol), and 2 M aqueous solution of Na ₂ CÜ3 (0.3 mL, 0.6 mmol) was heated in the microwave at 150°C for 60 minutes. The solvent was removed in vacuo, and after chromatography on silica gel, 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)- was obtained. [2,3'-bipyridine]-6-carboxamide as a light gray solid: 328.8 mg (88% yield); ^1H NMR (300 MHz, DMSO-ofe) δ 12.48 (s, 1H), 9.60 (s, 1H), 8.83-8.80 (m, 2H), 8.61 (ddd , J = 9.9, 2.1,2.1 Hz, 1H), 8.56 (s, 1H), 8.45 (dd, J = 7.1, 1.6 Hz, 1H), 8.28 -8.21 (m, 2H), 8.08 (d, J =7.9 Hz, 1H), 7.96 (td, J =7.9, 1.6 Hz, 1H), 7.46-7.42 (m, 1H), 3.99 (s, 4H); LRMS (M+H) m/z 375.62.

Example 4

5'-Cyano-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide(I-4)

0.1 mmol scale, with (5-methyl-1H-pyrazol-4-yl)boronic acid, 2.6 mg, 6.8% yield. (300 MHz, DMSÜ-ofe) δ 12.54 (s, 1H), 9.97 (s, 1H), 9.28 (d, J = 1.9 Hz, 1H), 9.18 (dd, J = 2,1,2.1 Hz, 1H), 8.85 (ad, J = 5.0 Hz, 1H), 8.59 (s, 1H), 8.52 (dd, J = 7.0, 1.8 Hz, 1H), 8.35 - 8.27 (m, 2H), 8.10 (ad, J= 7.9 Hz, 1H), 7.99 (ddd, J= 7.9, 7.9, 1.7 Hz, 1H), 7.46 (ddd, J= 7.4, 5.0, 1.3 Hz, 1H), 4.02 (s, 3H); LRMS (M+H) m/

Example 5

N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(pyrimidin-5-yl)picolinamide (I-5)

0.1 mmol scale, with pyrimidin-5-ylboronic acid, 5.8 mg, 16% yield. ofe) δ 12.52 (s, 1H), 9.80 (s, 2H), 9.43 (s, 1H), 8.81 (d, J = 5.7 Hz, 1H), 8.56 (s, 1H), 8.49 (dd, J = 7.4, 1.3 Hz, 1H), 8.32 - 8.23 (m, 2H), 8.08 (d, J = 8.9 Hz, 1H), 7.97 (ddd, J = 8,1,8,1, 1.7 Hz, 1H), 7.47 (ddd, J = 7.4, 5.0, 1.1 Hz , 1H), 4.01 (s, 4H); LRMS (M+H) m/z 8._

Example 6

N-(1 -methyl-3 -(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-5-yl)picolinamide (I-6)

0.1 mmol scale, with (1H-pyrazol-5-yl)boronic acid, 12.2 mg, 35% yield. ofe) 5 13.28 (s, 1H), 12.48 (s, 1H), 8.83 (s, 1H), 8.58 (s, 1H), 8.23 (dd, J = 6, 9, 2.2 Hz, 1H), 8.17 - 8.04 (m, 4H), 7.97 (ddd, J = 7.8, 7.8, 1.7 Hz, 1H), 7.45 (ddd, J = 7.3, 5.0, 1.0 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 4.01 (s, 3H); LRMS (M+H) m/z6.57._

Example 7

6-(3-methyl-1 H-pyrazol-5-yl)-N-(1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide (I-7)

Example 8

6-(1 -methyl-1 H-pyrazol-4-yl)-N-(1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide (I-8)

0.1 mmol scale, with (1-methyl-1H-pyrazol-4-yl)boronic acid, 5.6 mg, 16% yield. ¹ H NMR (300 MHz, DMSO-ofe) δ 12.38 (s, 1H), 8.75 (ad, J= 4.9 Hz, 1H), 8.57 (s, 1H), 8.48 ( s, 1H), 8.29 (s, 1H), 8.10 - 8.05 (m, 2H), 8.01 - 7.96 (m, 2H), 7.93 (dd, J = 7, 7, 1.2 Hz, 1H), 7.51-7.46 (m, 1H), 4.03 (s, 3H), 4.01 (s, 3H); LRMS (M+H) m/z 360.65. Example 9

N-(1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide (I-9)

A dioxane (4.5 mL) solution of 6-bromo-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (107.5 mg, 0.3 mmol), (1H-pyrazol-4-yl)boronic acid (50.4 mg, 0.45 mmol), Pd(PPh3)4 (34.7 mg, 0.03 mmol), and 2 M aqueous Na solution ₂ 03 (0.45 mL, 0.9 mmol) was microwaved at 150°C for 45 minutes. The solid was removed by filtration through a pad of celite, washing with MeOH. The filtrate was collected, the solvent was removed in vacuo, after chromatography on silica gel, N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6 was obtained. -(1H-pyrazol-4-yl)picolinamide as a pale yellow solid: 93.4 mg (90% yield): ¹ H Rm N (300 MHz, DMSO-ofe) 513.31 (s, 1H), 12, 38 (s, 1H), 8.76 (ddd, J = 5.0, 1.7, 1.0 Hz, 1H), 8.58 (s, 1H), 8.56 (d, J = 1, 3 Hz, 1H), 8.36 (d, J = 1.7 Hz, 1H), 8.12 - 8.05 (m, 2H), 8.02 - 7.96 (m, 3H), 7, 47 (ddd, J =7.4, 5.0, 1.3Hz, 1H), 4.01 (s, 3H); LRMS (M+H) m/z 346.59. Example 10

N-(1 -methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrrol-2-yl)picolinamide (I-10)

0.08 mmol scale, with (1H-pyrrol-2-yl)boronic acid, 19.5 mg, 71% yield. ¹ H NMR (300 MHz, DMSO-ofe) δ 12.42 (s, 1H), 11.56 (s, 1H), 8.74 (ddd, J= 5.0, 1.7, 0.9 Hz , 1H), 8.56 (s, 1H), 8.09 - 8.03 (m, 2H), 8.00 - 7.90 (m, 3H), 7.46 (ddd, J = 7.4 , 5.0, 1.3 Hz, 1H), 7.15-7.12 (m, 2H), 6.37 (ddd, J = 3.3, 2.4, 2.4 Hz, 1H), 4.01 (s, 3H); LRMS (M+H) m/z 345.56.

Example 11

N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrrol-3-yl)picolinamide (I-11)

0.08 mmol scale, with (1H-pyrrol-3-yl)boronic acid, 9.4 mg, 34% yield. ¹ H NMR (300 MHz, DMSO- de) δ 12.37 (s, 1H), 11.33 (s, 1H), 8.82 (ddd, J = 5.0, 1.7, 1.0 Hz , 1H), 8.58 (s, 1H), 8.09 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 8.01 -7.95 (m, 2H) , 7.90 - 7.87 (m, 2H), 7.74 (ddd, J = 2.8, 1.8, 1.8 Hz, 1H), 7.45 (ddd, J = 7.4, 5.0, 1.3 Hz, 1 H), 7.02 (dd, J = 2.5, 2.5 Hz, 1 H), 6.95 (ddd, J = 2.6, 1.6, 1.6Hz, 1H), 4.01 (s, 3H); LRMS (M+H) m/z 345.60.

Example 12

5'-methyl-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide(I-12)

0.3 mmol scale, with (5-methylpyridin-3-yl)boronic acid, 95.7 mg, 86% yield. ^1H NMR (300 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.55 (s, 1H), 8.81 (ddd, J = 4.9, 1.6, 1.0 Hz, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.58 (s, 1H), 8.48 (dd, J = 1.6, 1.6 Hz, 1H), 8.38 (dd, J = 7.1, 1.8 Hz, 1H), 8.27 - 8.19 (m, 2H), 8.09 (ddd, J = 8.1, 1.0, 1 .0 Hz, 1H), 7.98 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.47 (ddd, J = 7.4, 5.0, 1.3 Hz, 1H), 4.02 (s, 3H), 2.51 (s, 3H); LRMS (M+H) m/z 371.64.

Example 13

Methyl 5'-bromo-[2,3'-bipyridine]-6-carboxylate

A dioxane/H2O (15/1.5 mL) solution of methyl 6-bromopicolinate (648.1 mg, 3 mmol), (5-bromopyridin-3-yl)boronic acid (726.5 mg, 3.6 mmol), Pd(PPh) ₃ )4 (173.2 mg, 0.15 mmol), and 2 M aqueous Na ₂ CO ₃ solution (0.795 mL, 7.5 mmol) was microwaved at 150°C for 60 minutes. The solvent was removed in vacuo, after chromatography on silica gel, the fractions with the desired product were triturated further in hexanes-EtOAc (ca. 9:0.5). The title compound was obtained as an off-white solid: 582.3 mg (66% yield): ^1H NMR (300 MHz, Chloroform-d) 59.12 (d, J = 1.9 Hz, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.59 (dd, J = 2,1,2.1 Hz, 1H), 8.15 (dd, J = 7.4, 1.4 Hz, 1H), 7.98 (dd, J = 7.9, 7.4 Hz, 1H), 7.92 (dd, J = 7.9, 1.4 Hz, 1H), 4.05 (s, 3H ); LRMS (M+H) m/z 295.28.

Example 14

Methyl 5'-cyclopropyl-[2,3'-bipyridine]-6-carboxylate

A toluene/H2O (3/0.3 mL) solution of methyl 5'-bromo-[2,3'-bipyridine]-6-carboxylate (35.2 mg, 0.12 mmol), MIDA ester cyclopropylboronic acid (35.5 mg, 0.18 mmol), Pd(OAc)2 (1.3 mg, 0.006 mmol), tricyclohexylphosphine (3.4 mg, 0.012 mmol), and potassium phosphate (89.2 mg, 0.42 mmol) was microwaved at 150°C for 30 minutes, followed by another 39 hours at 100°C, after adding additional MIDA ester and catalysts, until that the reaction was complete as monitored by LC-MS. The solvent was removed in vacuo, after chromatography on silica gel the title compound was obtained as a light yellow sticky solid: ^1H NMR (300 ^{MHz, Chloroform-o) 5 8.96 (d,} J ^{= 2, 1 Hz, 1 H), 8.47 (d,} J ^{= 2.2 Hz, 1 H), 8.11 (dd,} J ^{= 7.1, 1.7 Hz, 1 H), 8.04 (ddd ,} J= ^{2.2, 2.2, 0.5 Hz, 1H), 7.95 (dd,} J ^{= 7.9, 7.1 Hz, 1H), 7.90 (dd,} J ^{= 7.9 , 1.7 Hz, 1H), 4.04 (s, 3H), 2.06 - 1.97 (m, 1H), 1.11- 1.05 (m, 2H), 0.87 - 0, 82(m, 2H); LRMS (M+H)} m/z ^255.36.

Example 15

5'-cyclopropyl-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-13)

A MeOH (0.5 mL) solution of methyl 5'-cyclopropyl-[2,3'-bipyridine]-6-carboxylate (~0.12 mmol) and aqueous NaOH solution (1 N, 126 μL) it was stirred at 50°C for 1 hour. The reaction was complete as monitored by LC-MS, the volatiles were removed in vacuo, and the crude product was used directly in the next reaction without further purification. A CH ² G ² (2 mL) solution of the acid, 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-amine di-hydrochloric acid (29.7 mg, 0.12 mmol ), HATU (55 mg, 0.14 mmol) and DIPEA (63 µL, 0.36 mmol) were stirred at room temperature for 1 hour, the reaction was complete as monitored by LC-MS. The solvent was removed in vacuo, after chromatography on silica gel the product was triturated further in hexanes-EtOAc. The title compound was obtained as a white solid: 7.9 mg (17% yield over 3 steps); ¹ H NMR (300 MHz, ^{DMSO-de) 12.61 (s, 1H), 9.55 (s, 1H), 8.84 (d, J} = ^{4.9 Hz, 1H), 8.61 ( d,} J ^{= 2.1 Hz, 1H), 8.57 (s, 1H), 8.40 (dd,} J ^{= 7.0, 1.9 Hz, 1H), 8.26 - 8.18 (m, 3H ), 8.08 (d,} J ^{= 8.0 Hz, 1H), 7.97 (ddd,} J ^{= 7.8, 7.8, 1.7 Hz, 1H), 7.45 (ddd,} J ^{= 7.3, 5.0, 1.2 Hz, 1H), 4.01 (s, 3H), 2.18 - 2.09 (m, 1H), 1.15 - 1.09 (m, 2H) , 0.98-0.95 (m, 2H); LRMS (M+H)} m/z ^397.59. Example 16

5'-(2-hydroxypropan-2-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridin]-6- carboxamide (I-14) 0.1 mmol scale, with 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)propan- 2-ol, 29.8 mg, 72% ^{yield. 1H NMR (300 MHz, DMSO-de) 12.62 (s, 1H), 9.64 (s, 1H), 8.93 (d, J} = ^{2.1 Hz, 1H), 8.91 (ddd ,} J ^{= 5.0, 1.7, 1.0 Hz, 1H), 8.59 - 8.58 (m, 2H), 8.39 (dd,} J ^{= 6.9, 2.1 Hz, 1 H), 8.28 - 8.21 (m, 2H), 8.08 (ddd,} J ^{= 8,1,8.1, 1.1 Hz, 1H), 7.97 (ddd,} J ^{= 7, 8, 7.8, 1.8 Hz, 1H), 7.45 (ddd,} J ^{= 7.4, 5.0, 1.3 Hz, 1H), 5.41 (s, 1H), 4.02 (s, 3H), 1.61 (s, 6H); LRMS (M+H)} m/z ^415.66.

Example 17

2'-methyl-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide (I-15)

0.08 mmol scale, with 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl)pyridine, 10.8 mg, 36% yield.

^{1HNMR (300 MHz, DMSO-de) 5 12.57 (s, 1H), 8.78 (d,} J ^{= 5.1 Hz, 1H), 8.66 (at d,} J ^{= 4.7 Hz, 1H), 8.55 (s, 1H), 8.41 -8.36 (m, 1H), 8.25 (d,} J ^{= 0.8 Hz, 1H), 8.24 (s, 1H), 8.15 - 8.12 (m, 2H), 8.06 (d,} J ^{= 8.0 Hz, 1H), 7.96 (ddd,} J ^{= 7.7, 7.7, 1.7 Hz, 1H), 7.46 (ddd,} J ^{= 7.3, 5.0, 1.3 Hz, 1H), 4.01 (s, 3H), 2.67 (s, 3H); LRMS (M+H)} m/z ^371.64.

Example 18

6'-methyl-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-16)

0.08 mmol scale, with (6-methylpyridin-3-yl)boronic acid, 20.4 mg, 69% yield. ¹ H NMR (300 MHz, DMSO-ofe) 512.55 (s, 1H), 9.58 (s, 1H), 8.84 (ddd, J = 5.0, 1.7, 0.9 Hz, 1H), 8.63 (dd, J = 8,1,2.4 Hz, 1H), 8.59 (s, 1H), 8.37 (dd, J = 7.2, 1.8 Hz, 1H), 8.25 - 8.17 (m, 2H), 8.10 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 7.99 (ddd, J = 7, 8, 7.8, 1.8 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.49 (ddd, J = 7.4, 5.0, 1.3 Hz , 1H), 4.02 (s, 3H), 2.67 (s, 3H); LRMS (M+H) m/z 371.67.

Example 19

N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(trifluoromethyl)-[2,3'-bipyridine]-6-carboxamide (I-17 )

0.08 mmol scale, with (5-(trifluoromethyl)pyridin-3-yl)boronic acid, 24.6 mg, 72% yield. 1H NMR (300 MHz, DMSO-ofe) 512.43 (s, 1H), 9.95 (s, 1H), 9.16 (s, 1H), 8.90 (s, 1H), 8.69 ( d, J = 4.8 Hz, 1H), 8.49 - 8.47 (m, 2H), 8.24 - 8.16 (m, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.90 (ddd, J = 7.9, 7.9, 1.5 Hz, 1H), 7.36 - 7.32 (m, 1H), 3.98 (s, 3H) ; LRMS (M+H) m/z 425.62.

Example 20

N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-(trifluoromethyl)-[2,4'-bipyridine]-6-carboxamide (I-18 )

0.08 mmol scale, with (2-(trifluoromethyl)pyridin-4-yl)boronic acid, 17.2 mg, 51% yield. 1H NMR (300 MHz, DMSO-ofe) 512.47 (s, 1H), 9.09 (d, J = 5.0 Hz, 1H), 8.63-8.60 (m, 2H), 8 .55 - 8.50 (m, 3H), 8.27 - 8.26 (m, 2H), 8.02 (d, J = 8.0 Hz, 1H), 7.92 (ddd, J = 7.8, 7.8, 1.7 Hz, 1H), 7.37 (ddd, J = 7.2, 5.0, 1.2 Hz, 1H), 3.99 (s, 3H) ; LRMS (M+H) m/z 425.67.

Example 21

5'-methoxy-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-19)

0.08 mmol scale, with (5-methoxypyridin-3-yl)boronic acid, 21.5 mg, 70% yield. 1H NMR (300 MHz, DMSO-ofe) δ 12.58 (s, 1H), 9.38 (d, J = 1.8 Hz, 1H), 8.88 (ddd, J = 5.0, 1, 7, 1.0 Hz, 1H), 8.59 (s, 1H), 8.56 (d, J = 2.8 Hz, 1H), 8.45 (dd, J = 7.1, 1, 8 Hz, 1H), 8.28 - 8.20 (m, 3H), 8.09 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 7.98 (ddd, J = 8,1,7,5, 1.8 Hz, 1H), 7.46 (ddd, J= 7.4, 5.0, 1.3 Hz, 1H), 4.03 (s, 3H ), 4.02 (s, 3H); LRMS (M+H) m/z 387.62.

Example 22

6'-methoxy-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-20)

0.08 mmol scale with (6-methoxypyridin-3-yl)boronic acid, 20.4 mg, 66% yield. 1H NMR (300 MHz, DMSO-ofe) 512.55 (s, 1H), 9.27 (dd, J = 2.5, 0.6 Hz, 1H), 8.80 (ddd, J = 5, 0, 1.7, 1.0 Hz, 1H), 8.69 (dd, J = 8.7, 2.5 Hz, 1H), 8.58 (s, 1H), 8.30 (dd, J = 7.6, 1.4 Hz, 1H), 8.19 (dd, J = 7.6, 7.6 Hz, 1H), 8.14 (dd, J = 7.6, 1.4 Hz , 1H), 8.08 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 7.97 (ddd, J = 8.1,7.5, 1.8 Hz, 1H), 7.48 (ddd, J = 7.4, 5.0, 1.3 Hz, 1H), 7.18 (dd, J = 8.7, 0.6 Hz, 1H), 4, 05 (s, 3H), 4.01 (s, 3H); LRMS (M+H) m/z 387.61.

Example 23

2'-Methoxy-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide (I-21)

0.08 mmol scale, with (2-methoxypyridin-4-yl)boronic acid, 16 mg, 52% yield. 1H NMR (300 MHz, DMSO-ofe) 512.52 (s, 1H), 8.86 (ddd, J = 5.0, 1.7, 1.0 Hz, 1H), 8.58 (s, 1H ), 8.50 (dd, J = 5.4, 0.6 Hz, 1H), 8.43 (dd, J = 5.5, 3.5 Hz, 1H), 8.27 (s, 1H) , 8.26 (d, J = 2.2 Hz, 1H), 8.08 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 7.99 (dd, J = 7 .4, 1.8 Hz, 1H), 7.94 (dd, J = 5.4, 1.5 Hz, 1H), 7.84 (dd, J = 1.4, 0.7 Hz, 1H) , 7.47 (ddd, J = 7.4, 5.0, 1.3 Hz, 1H), 4.05 (s, 3H), 4.01 (s, 3H); LRMS (M+H) m/z 387.52.

Example 24

5'-Isopropoxy-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-22)

0.3 mmol scale, with (5-isopropoxypyridin-3-yl)boronic acid, 99.3 mg, 80% yield. 1H NMR (300 MHz, DMSO-ofe) δ 12.54 (s, 1H), 9.31 (d, J = 1.8 Hz, 1H), 8.93 (ddd, J = 4.9, 1, 6, 0.9 Hz, 1H), 8.59 (s, 1H), 8.54 (d, J = 2.7 Hz, 1H), 8.45 (dd, J = 6.6, 2.3 Hz, 1H), 8.27 - 8.21 (m, 3H), 8.10 (ddd, J = 8.1,0.9, 0.9 Hz, 1H), 7.98 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.44 (ddd, J = 7.4, 5.0, 1.2 Hz, 1H), 4.97 (hept, J = 6.0Hz, 1H), 4.02 (s, 3H), 1.41 (d, J = 6.0Hz, 6H); LRMS (M+H) m/z 415.67.

Example 25

N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-((tetrahydro-2H-pyran-4-yl)oxy)-[2,3' - bipyridine]-6-carboxamide (I-23)

0.3 mmol scale, with (5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)boronic acid, 110.4 mg, 81% yield. ¹ H NMR (300 MHz, DMSO-ofe) 512.55 (s, 1H), 9.34 (d, J = 1.7 Hz, 1H), 8.92 (ddd, J= 5.0, 1, 6, 0.9Hz, 1H), 8.61 (d, J= 2.7 Hz, 1H), 8.60 (s, 1H), 8.46 (dd, J= 6.8, 2.1 Hz, 1H), 8.31 - 8.29 (m, 1H), 8.28 - 8.21 (m, 2H), 8.10 (ad, J= 8.0 Hz, 1H), 7.99 (ddd, J =7, 7, 7.7, 1.7 Hz, 1H), 7.44 (ddd, J = 7.4, 5.0, 1.2 Hz, 1H), 4.92 (tt, J = 8.5 , 4.1 Hz, 1H), 4.02 (s, 3H), 3.94 (sd, J = 11.7, 4.2 Hz, 2H), 3.55 (ddd, J = 11.7 , 9.5, 2.6 Hz, 2H), 2.15-2.10 (m, 2H), 1.71 (dtd, J =13.0, 9.5, 4.1 Hz, 2H); LRMS (M+H) m/z 457.61.

Example 26

N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(2,2,2-trifluoroethoxy)-[2,3'-bipyridin]-6 -carboxamide (I-24)

0.1 mmol scale, with (5-(2,2,2-trifluoroethoxy)pyridin-3-yl)boronic acid, 30.8 mg, 68% yield. 1H NMR (300 MHz, DMSO-ofe) δ 12.55 (s, 1H), 9.29 (d, J = 2.4 Hz, 1H), 8.81-8.77 (m, 2H), 8.58 (s, 1H), 8.35 (dd, J = 7.5, 1.3 Hz, 1H), 8.22 (dd, J = 7.6, 7.6 Hz, 1H), 8 .17 (dd, J = 7.9, 1.1 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.98 (ddd, J = 7.7, 7.7 , 1.6 Hz, 1H), 7.49 (ddd, J = 6.7, 4.7, 1.0 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 5 .21 (c, J = 9.1 Hz, 2H), 4.01 (s, 3H); LRMS (M+H) m/z 455.53.

Example 27

5'-amino-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-25)

0.08 mmol scale, with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine, 13.3 mg, 45% yield.1H NMR (300 MHz, DMSO-ofe) δ 12.67 (s, 1H), 8.86 (d, J = 1.9 Hz, 1H), 8.81 (ddd, J = 5.0, 1.7 , 0.9 Hz, 1H), 8.58 (s, 1H), 8.24 - 8.15 (m, 4H), 8.07 (ddd, J= 8.1, 1.1, 1.1 Hz, 1H), 7.97 (ddd, J= 7.7, 7.7, 1.8 Hz, 1H), 7.73 -7.71 (m, 1H), 7.43 (ddd, J = 7.4, 5.0, 1.3Hz, 1H), 5.60 (s, 2H), 4.03 (s, 3H); LRMS (M+H) m/z 372.64.

Example 28

N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(methylamino)-[2,3'-bipyridine]-6-carboxamide (I-26 )

An NMP (1 mL) solution of 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide (22.5 mg, 0.06 mmol), methylamine hydrochloride (>5 eq.) and NaHCO ₃ (>2 eq.) was heated at 150-180°C for 20 days until >50% formed. of the desired product, as monitored by LC-MS. The solvent was removed in vacuo, after chromatography on silica gel the title compound was obtained as a beige solid: 14 mg (61% yield.); 1H NMR (300 MHz, DMSO-ofe) 512.66 (s, 1H), 8.97 (d, J = 1.9 Hz, 1H), 8.81 (ddd, J = 5.0, 1.7 , 1.0 Hz, 1H), 8.58 (s, 1H), 8.29 (dd, J = 7.1,2.0 Hz, 1H), 8.25 - 8.17 (m, 3H ), 8.08 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 7.97 (ddd, J = 8,1,7.5, 1.8 Hz, 1H), 7.61 -7.60(m, 1H), 7.44 (ddd, J =7.4, 5.0, 1.3 Hz, 1H), 6.18 (c, J = 5.0 Hz, 1H), 4.02 (s, 3H), 2.85 (d, J =5.0 Hz, 3H); LRMS (M+H) m/z 386.68.

Example 29

5'-(cyclopropylamino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-27)

An NMP (1 mL) solution of 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide (22.5 mg, 0.06 mmol), cyclopropanamine (>5 eq.) and NaHCO ₃ (>2 eq.) was heated at 140-150°C for 12 days until >50% product was formed. desired, as monitored by LC-MS. The solvent was removed in vacuo, after chromatography on silica gel and further trituration with hexanes-EtOAc, the title compound was obtained as an off-white solid: 1.8 mg (7% yield.); 1H NMR (300 MHz, DMSO-afe) 512.67 (s, 1H), 9.00 (d, J = 1.9 Hz, 1H), 8.80 (ddd, J= 5.0, 1.7 , 0.9 Hz, 1H), 8.58 (s, 1H), 8.30 (d, J = 2.6 Hz, 1H), 8.24-8.19 (m, 3H), 8.08 (ddd, J= 8.1, 1.1, 1.1 Hz, 1H), 7.97 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.76 - 7 .75 (m, 1H), 7.42 (ddd, J= 7.3, 5.0, 1.2 Hz, 1H), 6.62 (d, J= 1.7 Hz, 1H), 4 .02 (s, 3H), 3.35 - 3.33 (m, overlapped with HzO, 1H), 0.84 - 0.78 (m, 2H), 0.52 - 0.48 (m, 2H) ; LRMS (M+H) m/z 412.73.

Example 30

5'-(isopropylamino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-28)

An NMP (1 mL) solution of 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide (22.5 mg, 0.06 mmol) and propan-2-amine (>5 eq.) was heated at 120-150°C for 24 days until >50% of the desired product was formed. The solvent was removed in vacuo, after silica gel chromatography and further trituration in hexanes-EtOAc the title compound was obtained as a light beige solid: 7.1 mg (29% yield): 1H NMR (300 MHz, DMSO-de) 512.66 (s, 1H), 8.90 (d, J= 1.9 Hz, 1H), 8.80 (ddd, J= 5.0, 1.7, 1 0.0 Hz, 1H), 8.58 (s, 1H), 8.27 - 8.16 (m, 4H), 8.08 (ddd, J= 8.1, 1.1, 1.1 Hz , 1H), 7.97 (ddd, J= 7.7, 7.7, 1.8 Hz, 1H), 7.66 - 7.64 (m, 1H), 7.43 (ddd, J= 7 .4, 5.0, 1.3 Hz, 1H), 5.95 (d, J = 8.3 Hz, 1H), 4.01 (s, 3H), 3.84 - 3.73 (m , 1H), 1.22 (d, J= 6.3 Hz, 6H); LRMS (M+H) m/z 414.73.

Example 31

5'-(tert-Butylamino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I -29)

0.1 mmol scale, with N-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine, 15.2 mg, 36% yield. 1H NMR (300 MHz, DMSO-ofe) δ 12.65 (s, 1H), 8.94 (d, J = 1.6 Hz, 1H), 8.82 (d, J = 4.4 Hz, 1H ), 8.58 (s, 1H), 8.32 (d, J= 2.6 Hz, 1H), 8.22 - 8.19 (m, 3H), 8.08 (bd, J= 8 .0 Hz, 1H), 7.97 (ddd, J= 7.8, 7.8, 1.7 Hz, 1H), 7.81 -7.79 (m, 1H), 7.43 (ddd, J = 7.3, 5.0, 1.0 Hz, 1H), 5.84 (bs, 1H), 4.02 (s, 3H), 1.42 (s, 9H); LRMS (M+H) m/z 428.66.

Example 32

N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5'-((tetrahydro-2H-pyran-4-yl)amino)-[2,3'- bipyridine]-6-carboxamide (I-30)

An NMP (1.5 mL) solution of 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridine ]-6-carboxamide (30 mg, 0.08 mmol) and tetrahydro-2H-pyran-4-amine 40 mg, 0.4 mmol) was heated at 150°C for 19 days until >50% product was formed desired, as monitored by LC-MS. The solvent was removed in vacuo, after chromatography on silica gel and further trituration with hexanes-EtOAc, the title compound was obtained as a light beige solid: 5mg (14% yield); 1H NMR (300 MHz, DMSO-afe) 512.66 (s, 1H), 8.93 (d, J = 1.8 Hz, 1H), 8.80 (ddd, J = 5.0, 1.7 , 0.9 Hz, 1H), 8.58 (s, 1H), 8.30 - 8.17 (m, 4H), 8.08 (ddd, J = 8.1, 1.0, 1, 0 Hz, 1H), 7.97 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.72 - 7.71 (m, 1H), 7.43 (ddd, J = 7.4, 5.0, 1.3 Hz, 1H), 6.10 (d, J = 8.3 Hz, 1H), 4.02 (s, 3H), 3.91 (ddd, J = 11.3, 3.2, 3.2 Hz, 2H), 3.75 - 3.63 (m, 1H), 3.47 - 3.36 (m, partially overlapped with H2O, 2H), 2.00 - 1.95 (m, 2H), 1.63 (s, 1H), 1.53-1.40 (m, 2H); LRMS (M+H) m/z 456.46.

Example 33

5'-((2-methoxyethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-31) An NMP (1.2 mL) solution of 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2, 3'-Bipyridine]-6-carboxamide (22.5 mg, 0.06 mmol) and 2-methoxyethane-1-amine (>5 eq) was heated at 140 - 150°C for 13 days until reaction was complete , as monitored by LC-MS. The solvent was removed in vacuo, after chromatography on silica gel and further trituration with hexanes-EtOAc, the title compound was obtained as a tan solid: 14 mg (54% yield)); 1H NMR (300 MHz, DMSO-ofe) δ 12.64 (s, 1H), 8.97 (d, J = 1.7 Hz, 1H), 8.82 (ddd, J= 5.0, 1, 6, 0.9 Hz, 1H), 8.57 (s, 1H), 8.28 - 8.16 (m, 4H), 8.07 (bd, J= 8.0 Hz, 1H), 7.96 (ddd, J = 7.8, 7.8, 1.7 Hz, 1H), 7.70 - 7.68 (m, 1H), 7.43 (ddd, J = 7.4 , 5.0, 1.2 Hz, 1H), 6.13 (t, J =5.7 Hz, 1H), 4.01 (s, 3H), 3.59 (t, J= 5, 5 Hz, 2H), 3.41-3.36 (m, partially overlapped with H2O, 2H), 3.34 (s, 3H); LRMS (M+H) m/z 430.72.

Example 34

5'-((cyclopropylmethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide ( I-32) A mixture of 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]-6- carboxamide (22.5 mg, 0.06 mmol) and cyclopropylmethanamine (1 mL) was heated at 150-180°C for 20 days until >50% of the desired product was formed, as monitored by LC-MS. The solvent was removed in vacuo, after chromatography on silica gel and further trituration with hexanes-EtOAc, the title compound was obtained as a beige solid: 8.6 mg (34% yield)); 1H NMR (300 MHz, DMSO-de) δ 12.65 (s, 1H), 8.94 (d, J = 1.7 Hz, 1H), 8.81 (d, J = 5.0 Hz, 1H ), 8.58 (s, 1H), 8.28 - 8.16 (m, 4H), 8.08 (bd, J = 8.2 Hz, 1H), 7.96 (ddd, J = 7 .5, 7.5, 1.3 Hz, 1H), 7.66 (dd, J = 2.1 Hz, 1H), 7.45 - 7.41 (m, 1H), 6.21 (t , J= 5.4 Hz, 1H), 4.01 (s, 3H), 3.09 - 3.05 (m, 2H), 1.20 - 1.07 (m, 1H), 0.57 - 0.51 (m, 2H), 0.30-0.26 (m, 2H); LRMS (M+H) m/z 426.75.

Example 35

N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-5'-((2,2,2-trifluoroethyl)amino)-[2,3'-bipyridine ]-6-carboxamide (I-33) 1H NMR (300 MHz, DMSO-afe) 512.64 (s, 1H), 9.10 (d, J = 1.7 Hz, 1H), 8.84 (d, J= 4.9 Hz, 1H) , 8.58 (s, 1H), 8.36 (d, J = 2.6 Hz, 1H), 8.32 (dd, J = 7.5, 1.5 Hz, 1H), 8.25 ( dd, J = 7.5, 7.5 Hz, 1 H), 8.20 (dd, J = 7.5, 1.6 Hz, 1 H), 8.08 (d, J = 8.1 Hz , 1H), 7.97 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.89 (dd, J = 2,1,2.1 Hz, 1H), 7.43 (ddd, J= 7.3, 5.0, 1.2 Hz, 1H), 6.79 (t, J= 6.9 Hz, 1H), 4.26 - 4.14 (m, 2H), 4.02 (s, 3H); LRMS (M+H) m/z 454.69.

Example 36

N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-5'-(methylsulfonamido)-[2,3'-bipyridine]-6-carboxamide (I-34 )

0.08 mmol scale, with N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide, 21.3 mg, 59% de performance. 1H NMR (300 MHz, DMSO-afe) δ 12.63 (s, 1H), 10.27 (s, 1H), 9.48 (d, J= 2.0 Hz, 1H), 8.83 (ddd , J= 5.0, 1.7, 1.0 Hz, 1H), 8.69 (d, J= 2.4 Hz, 1H), 8.59 (s, 1H), 8.36 - 8.35 (m, 1H), 8.31 - 8.23 (m, 3H), 8.08 (ddd, J= 8.1, 1.1, 1.1 Hz, 1H), 7.97 ( ddd, J = 8,1,7.5, 1.8 Hz, 1H), 7.43 (ddd, J= 7.4, 5.0, 1.3 Hz, 1H), 4.02 (s , 3H), 3.20 (s, 3H); LRMS (M+H) m/z 450.67.

Example 37

5'-(dimethylamino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-35 )

An NMP (1 mL) solution of 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide (22.5 mg, 0.06 mmol), dimethylamine hydrochloride (>5 eq.) and NaHCO ₃ (>2 eq.) was heated at 120-150°C for 11 days until >50% formed. of the desired product, as monitored by LC-MS. The solvent was removed in vacuo, after chromatography on silica gel and further trituration with hexanes-EtOAc, the title compound was obtained as a tan solid: 4.3 mg (18% yield)); 1H NMR (300 MHz, DMSO-afe) δ 12.65 (s, 1H), 9.12 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 4.9 Hz, 1 H), 8.58 (s, 1H), 8.40 (dd, J = 7.2, 1.8 Hz, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8 .26 -8.18 (m, 2H), 8.09 (d, J = 8.0 Hz, 1 H), 7.97 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.80 - 7.79 (m, 1H), 7.44 (ddd, J= 7.4, 5.0, 1.2 Hz, 1H), 4.02 (s, 3H ), 3.08 (s, 6H); LRMS (M+H) m/z 400.66.

Example 38

N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-5'-(pyrrolidin-1-yl)-[2,3'-bipyridine]-6-carboxamide (I-36)

An NMP (1 mL) solution of 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide (22.5 mg, 0.06 mmol) and pyrrolidine (0.1 mL) was heated at 120-150°C for 4 days until reaction was complete, as monitored by LC-mS. Solvent was removed in vacuo, after chromatography on silica gel and further trituration with hexanes-EtOAc, the title compound was obtained as a yellow solid: 14.9 mg (58% yield): 1H NMR (300 MHz, DMSO -afe) δ 12.66 (s, 1H), 9.06 (d, J= 1.8 Hz, 1H), 8.81 (ddd, J = 5.0, 1.7, 0.9 Hz, 1H), 8.58 (s, 1H), 8.37 (dd, J = 7.2, 1.8 Hz, 1H), 8.25 - 8.17 (m, 3H), 8.08 (ddd , J = 8.1, 1.1, 1.1 Hz, 1H), 7.97 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.60 - 7, 59 (m, 1H), 7.44 (ddd, J = 7.4, 5.0, 1.3 Hz, 1H), 4.02 (s, 3H), 3.44 - 3.39 (m, 4H), 2.05-2.01 (m, 4H); LRMS (M+H) m/z 426.69.

Example 39

N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-5'-morpholino-[2,3'-bipyridine]-6-carboxamide (I-37)

An NMP (1 mL) solution of 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide (22.5 mg, 0.06 mmol) and morpholine (0.1 mL) was heated at 120-150°C for 11 days until reaction was complete, as monitored by LC-MS. The solvent was removed in vacuo, after chromatography on silica gel and further trituration with hexanes-EtOAc, the title compound was obtained as an off-white solid: 21.4 mg (87% yield)); 1H NMR (300 MHz, DMSO-afe) δ 12.64 (s, 1H), 9.23 (d, J = 1.7 Hz, 1H), 8.82 (bd, J = 5.0 Hz, 1H ), 8.58 (s, 1H), 8.54 (d, J = 2.7 Hz, 1H), 8.42 (dd, J = 7.2, 1.7 Hz, 1H), 8 .26 - 8.18 (m, 2H), 8.10 - 8.07 (m, 2H), 7.98 (ddd, J= 7.7, 7.7, 1.7 Hz, 1H), 7 .46 (ddd, J= 7.4, 5.0, 1.2 Hz, 1H), 4.02 (s, 3H), 3.84 - 3.81 (m, 4H), 3.37 - 3 .34(m, partially overlapped with H2O, 2H), 3.34 (s, 4H); LRMS (M+H) m/z 442.59.

Example 40

N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(4-methylpiperazin-1-yl)-[2,3'-bipyridin]-6 -carboxamide (I-38)

An NMP (1 mL) solution of 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide (22.5 mg, 0.06 mmol) and 1-methylpiperazine (0.1 mL) was heated at 120-150°C for 11 days until >50% of the desired product was formed, as monitored by LC-MS. The solvent was removed in vacuo, after chromatography on silica gel and further trituration with hexanes-EtOAc, the title compound was obtained as a light tan solid: 12.4 mg (45% yield); 1H NMR (300 MHz, DMSO-afe) δ 12.64 (s, 1H), 9.19 (d, J= 1.7 Hz, 1H), 8.81 (ddd, J = 4.9, 1, 6, 0.9 Hz, 1H), 8.58 (s, 1H), 8.53 (d, J = 2.7 Hz, 1H), 8.41 (dd, J= 7.0, 1.9 Hz, 1H), 8.26 - 8.18 (m, 2H), 8.10 - 8.07 (m, 2H), 7.98 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.45 (ddd, J= 7.4, 5.0, 1.3 Hz, 1H), 4.02 (s, 3H), 3.38 -3.35 (m, partially overlapped with H2O, 4H), 2.56-2.52 (m, overlapped with DMSO, 4H), 2.28 (s, 3H); LRMS (M+H) m/z 455.77.

Example 41

N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(methylsulfonyl)-[2,3'-bipyridine]-6-carboxamide (I-39 )

0.1 mmol scale, with (5-(methylsulfonyl)pyridin-3-yl)boronic acid, 26.1 mg, 45% yield. 1H NMR (300 MHz, DMSO-afe) 512.58 (s, 1H), 10.02 (d, J = 2.1 Hz, 1H), 9.31 (d, J = 2.1 Hz, 1H ), 9.05 (dd, J = 2,1,2.1 Hz, 1H), 8.83 (ddd, J = 5.0, 1.7, 1.0 Hz, 1H), 8.59 (s, 1H), 8.54 (dd, J = 6.7, 2.2 Hz, 1H), 8.35 - 8.28 (m, 2H), 8.08 (ddd, J = 8, 1, 1.1, 1.1 Hz, 1H), 7.97 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H), 7.43 (ddd, J = 7.4, 5.0, 1.3Hz, 1H), 4.02 (s, 3H), 3.50 (s, 3H); LRMS (M+H) m/z 435.45.

Example 42

N6-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5',6-dicarboxamide (I-40)

Example 43

N6-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4'-bipyridine]-2',6-dicarboxamide (I-41)

Example 44

2'-Cyano-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide(I-42)

Example 45

6'-amino-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-43)

0.1 mmol scale, with (6-aminopyridin-3-yl)boronic acid, 18.8 mg, 51% yield.1H NMR (300 MHz, DMSO- de) 512.49 (s, 1H), 9.14 (d, J = 2.2 Hz, 1H), 8.84 (dd, J = 4.9 Hz, 1H), 8.58 (s, 1H), 8.36 (dd, J = 8.7, 2.5 Hz, 1H), 8.14 (dd, J = 7.8, 1.6 Hz, 1H), 8.13 - 7.94 (m, 4H), 7.44 (ddd, J = 7.4, 5.0, 1.2 Hz, 1H), 6.70 (d, J = 8.7 Hz, 1H), 6.53 (s, 2H), 4.01 (s, 3H); LRMS (M+H) m/z 372.50.

Example 46

N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide (I -44)

0.1 mmol scale, with (1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid, 26.1 mg, 66% yield. 1H NMR (300 MHz, DMSO-ofe) 512.64 (s, 1H), 12.06 (s, 1H), 9.46 (d, J = 2.1 Hz, 1H), 8.95 (ddd, J = 5.0, 1.7, 0.9 Hz, 1H), 8.92 (d, J = 2.0 Hz, 1H), 8.60 (s, 1H), 8.39 (dd, J = 7.7, 1.2 Hz, 1H), 8.20 (dd, J = 7.7, 7.7 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 8 .11 (d, J = 8.2 Hz, 1H), 8.00 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.66 (dd, J= 3, 3, 2.6 Hz, 1H), 7.46 (ddd, J = 7.4, 5.0, 1.3 Hz, 1H), 6.67 (dd, J = 3.4, 1.8 Hz, 1H), 4.03 (s, 3H); LRMS (M+H) m/z 396.57.

Example 47

N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrrolo[3,2-b]pyridin-6-yl)picolinamide (I -Four. Five)

0.1 mmol scale, with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine, 9.7 mg , 25% yield. 1H NMR (300 MHz, DMSO-ofe) δ 12.67 (s, 1H), 11.68 (s, 1H), 9.60 (d, J= 2.0 Hz, 1H), 8.93 (ddd , J= 5.0, 1.6, 0.9 Hz, 1H), 8.60 - 8.59 (m, 2H), 8.38 (dd, J= 7.6, 1.3 Hz, 1H ), 8.21 (dd, J= 7.6, 7.6 Hz, 1 H), 8.15 (dd, J= 7.6, 1.3 Hz, 1 H), 8.10 (ddd, J= 8.1, 1.1, 1.1 Hz, 1H), 7.98 (ddd, J= 7.7, 7.7, 1.8 Hz, 1H), 7.87 - 7.85 ( m, 1H), 7.47 (ddd, J= 7.4, 5.0, 1.3 Hz, 1H), 6.78 - 6.77 (m, 1H), 4.03 (s, 3H ); LRMS (M+H) m/z 396.59.

Example 48

6-(1 H-indol-5-yl)-N-(1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide (I-46)

0.1 mmol scale, with (1H-indol-5-yl)boronic acid, 27.9 mg, 70% yield. 1H NMR (300 MHz, DMSO-ofe) 5 12.67 (s, 1H), 11.40 (s, 1H), 8.85 (ddd, J= 5.0, 1.6, 0.9 Hz , 1H), 8.65 (d, J =1.3 Hz, 1H), 8.60 (s, 1H), 8.29 (dd, J= 7.7, 1.3 Hz, 1H) , 8.20 (dd, J= 8.6, 1.7 Hz, 1H), 8.16 - 8.07 (m, 3H), 8.00 (ddd, J= 7.7, 7.7, 1.8 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.54-7.52(m, 1H), 7.46 (ddd, J= 7.4, 5.0, 1.2 Hz, 1H), 6.65-6.64 (m, 1H), 4.02 (s, 3H); LRMS (M+H) m/z 395.57. Example 49

6-(1 H-indol-6-yl)-N-(1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide (I-47)

0.1 mmol scale, with (1H-indol-6-yl)boronic acid, 37.8 mg, 96% yield. 1H NMR (300 MHz, DMSO-ofe) 5 12.69 (s, 1H), 11.44 (s, 1H), 8.76 (ad, J= 4.9 Hz, 1H), 8.60 ( s, 1H), 8.32 (s, 1H), 8.27 (dd, J = 7.6, 1.4 Hz, 1H), 8.20 -8.07 (m, 4H), 7.98 (ddd, J= 7.7, 7.7, 1.7 Hz, 1H), 7.87 (d, J= 8.3 Hz, 1H), 7.56 (dd, J =2.7, 2.7 Hz, 1H), 7.45 (ddd, J= 7.3, 5.0, 1.2 Hz, 1H), 6.61 - 6.60 (m, 1H), 4.02 (s, 3H); LRMS (M+H) m/z 395.54.

Example 50

N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-phenylpicolinamide (I-48)

0.08 mmol scale, with phenylboronic acid, 20.5 mg, 72% yield. 1H NMR (300 MHz, DMSO-ofe) δ 12.58 (s, 1H), 8.75 (ddd, J= 5.0, 1.7, 1.0 Hz, 1H), 8.59 (s , 1H), 8.45 - 8.42 (m, 2H), 8.32 (dd, J= 6.9, 2.1 Hz, 1H), 8.24 - 8.17 (m, 2H), 8.09 (ddd, J= 8.0, 1.1, 1.1 Hz, 1H), 7.98 (ddd, J= 7.7, 7.7, 1.8 Hz, 1H), 7 .75 - 7.70 (m, 2H), 7.66 - 7.61 (m, 1H), 7.49 (ddd, J= 7.4, 5.0, 1.3 Hz, 1H), 4.02 (s, 3H); LRMS (M+H) m/z 356.59.

Example 51

N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(m-tolyl)picolinamide (I-49)

0.08 mmol scale, with m-tolylboronic acid, 15.8 mg, 71% yield. 1H NMR (300 MHz, DMSO-ofe) 5 12.63 (s, 1H), 8.67 (bd, J= 4.9 Hz, 1H), 8.58 (s, 1H), 8.29 - 8 .17 (m, 4H), 8.12 (s, 1H), 8.07 (d, J= 8.1 Hz, 1H), 7.97 (ddd, J= 7.7, 7.7, 1 0.8 Hz, 1H), 7.61 (dd, J= 7.6, 7.6 Hz, 1H), 7.48 - 7.43 (m, 2H), 4.02 (s, 3H), 2.51 (s, 3H); LRMS (M+H) m/z 370.63.

Example 52

N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(p-tolyl)picolinamide (I-50)

0.08 mmol scale, with p-tolylboronic acid, 22.1 mg, 75% yield. 1H NMR (300 MHz, DMSO-ofe) 5 12.64 (s, 1H), 8.68 (ad, J= 4.9 Hz, 1H), 8.58 (s, 1H), 8.28 ( dd, J= 6.7, 2.4 Hz, 1H), 8.25 - 8.17 (m, 3H), 8.13 (s, 1H), 8.08 (d, J= 8.1 Hz , 1H), 7.98 (ddd, J= 7.7, 7.7, 1.8 Hz, 1H), 7.62 (dd, J = 7.6, 7.6 Hz, 1H), 7 .48-7.43 (m, 2H), 4.02 (s, 3H), 2.51 (s, 3H); LRMS (M+H) m/z 370.18.

Example 53

6-(3-methoxyphenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (I-51)

0.08 mmol scale, with (3-methoxyphenyl)boronic acid, 2.2 mg, 7% yield. 1H NMR (300 MHz, DMSO-ofe) δ 12.58 (s, 1H), 8.82 (ad, J= 5.0 Hz, 1H), 8.59 (s, 1H), 8.33 (dd , J= 6.4, 2.7 Hz, 1H), 8.23 - 8.17 (m, 2H), 8.08 (d, J= 8.0 Hz, 1H), 8.01 - 7 .94 (m, 3H), 7.65 (dd, J= 8.0, 8.0 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.23 (dd, J= 8 ,1,2.6 Hz, 1H), 4.02 (s, 3H), 3.95 (s, 3H); LRMS (M+H) m/z 386.58.

Example 54

6-(4-methoxyphenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (I-52)

0.08 mmol scale, with (4-methoxyphenyl)boronic acid, 16 mg, 52% yield.1H NMR (300 MHz, DMSO-afe) δ 12.54 (s, 1H), 8.77 - 8, 75 (m, 1H), 8.58 (s, 1H), 8.40 - 8.37 (m, 2H), 8.24 (dd, J= 7.5, 1.6 Hz, 1H), 8.17 - 8.07 (m, 3H), 7.98 (ddd, J= 7.5, 7.5, 1.7 Hz, 1H), 7.51 (ddd, J= 7.4, 5.0, 1.3 Hz, 1H), 7.27-7.24 (m, 2H), 4.01 (s, 3H), 3.94 (s, 3H);

LRMS (M+H) m/z 386.64.

Example 55

6-(3-cyanophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (I-53)

0.08 mmol scale, with (3-cyanophenyl)boronic acid, 21 mg, 69% yield. 1H NMR (300 MHz, DMSO-afe) δ 12.46 (s, 1H), 8.73-8.66 (m, 3H), 8.53 (s, 1H), 8.37 (dd, J = 6.1,2.7 Hz, 1H), 8.24 - 8.17 (m, 2H), 8.07 - 8.03 (m, 2H), 7.97 - 7.86 (m, 2H ), 7.41-7.37 (m, 1H), 4.00 (s, 3H); LRMS (M+H) m/z 381.61.

Example 56

6-(4-cyanophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (I-54)

0.08 mmol scale, with (3-cyanophenyl)boronic acid, 9.1 mg, 30% yield. 6) 512.50 (s, 1H), 8.72 (ad, J = 5.2 Hz, 1H), 8.60 - 8.57 (m, 2H), 8.43- 8.36 (m, 1H), 8.27 - 8.19 (m, 3H), 8.08 (d, J = 7.9 Hz, 1H), 8.00 - 7.96 (m, 1H), 7.69 - 7.58 (m, 2H), 7.53 - 7.49 (m, 1H), 4.02 (s, 3H); LRMS (M+H) m/z6.

Example 57

6-(3-fluorophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (I-55)

0.08 mmol scale, with (3-fluorophenyl)boronic acid, 20.7 mg, 69% yield. 1H NMR (300 MHz, DMSO-afe) 512.51 (s, 1H), 8.75 (ddd, J = 5.0, 1.7, 1.0 Hz, 1H), 8.59 (s, 1H), 8.37 (dd, J = 6.3, 2.7 Hz, 1H), 8.27 - 8.21 (m, 4H), 8.09 (ddd, J = 8.1, 1 .1, 1.1 Hz, 1H), 7.98 (ddd, J = 8,1,7.5, 1.8 Hz, 1H), 7.79 - 7.72 (m, 1H), 7, 50 - 7.43 (m, 2H), 4.02 (s, 3H); LRMS (M+H) m/z 374.64.

Example 58

6-(4-fluorophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (I-56)

0.08 mmol scale, with (4-fluorophenyl)boronic acid, 22 mg, 74% yield. (300 MHz, DMSO-afe) δ 12.52 (s, 1H), 8.72 (ddd, J = 5.0, 1.6, 0.9 Hz, 1H), 8.58 (s, 1H ), 8.49 - 8.44 (m, 2H), 8.30 (dd, J = 7.0, 2.0 Hz, 1H), 8.22 - 8.15 (m, 2H), 8, 08 (ad, J = 8.0 Hz, 1 H), 7.98 (ddd, J = 7.7, 7.7, 1.8 Hz, 1 H), 7.60 - 7.54 (m, 2H), 7.50 (ddd, J =7.3, 5.0, 1.3 Hz, 1H), 4.01 (s, 3H); LRMS (M+H)4.

Example 59

6-(3-aminophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (I-57)

0.08 mmol scale, with (3-aminophenyl)boronic acid, 18 mg, 61% yield. 1H NMR (300 MHz, DMSO-afe) δ 12.68 (s, 1H), 8.75 (bd, J = 4.8 Hz, 1H), 8.58 (s, 1H), 8.19 - 8.05 (m, 4H), 7.96 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.56 (bd, J = 7.7 Hz, 1H), 7 .47 (dd, J = 1.9, 1.9 Hz, 1H), 7.42 (ddd, J = 7.4, 5.0, 1.2 Hz, 1H), 7.36 (dd, J = 7.8, 7.8 Hz, 1H), 6.83 (dd, J = 7.6, 1.7 Hz, 1H), 5.33 (s, 2H), 4.01 (s, 3H) ; LRMS (M+H) m/z 371.60.

Example 60

N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(3-(methylamino)phenyl)picolinamide (I-58)

1H NMR (300 MHz, DMSO-afe) δ 12.68 (s, 1H), 8.68 (bd, J = 4.9 Hz, 1H), 8.58 (s, 1H), 8.18-8 .13 (m, 3H), 8.06 (bd, J = 8.0 Hz, 1H), 7.96 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7 .64 (d, J = 7.7 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.36 (dd, J = 1.8, 1.8 Hz, 1H), 6, 79 (dd, J = 7.7, 1.9 Hz, 1H), 5.88 - 5.86 (m, 1H), 4.01 (s, 3H), 2.80 (d, J = 4 .2Hz, 3H); LRMS (M+H) m/z 385.68.

Example 61

6-(3-(dimethylamino)phenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (I-59)

0.08 mmol scale, with (3-(dimethylamino)phenyl)boronic acid, 13.2 mg, 41% yield. 1H NMR (300 MHz, DMSO-afe) 512.66 (s, 1H), 8.65 (ddd, J = 4.9, 1.7, 0.9 Hz, 1H), 8.58 (s, 1H ), 8.28 (dd, J = 6.8, 2.3 Hz, 1H), 8.20 - 8.14 (m, 2H), 8.07 (ddd, J = 8.1, 1.0 , 1.0 Hz, 1 H), 7.97 (ddd, J = 7.7, 7.7, 1.8 Hz, 1 H), 7.78 (dd, J = 7.8 Hz, 1 H ), 7.57 - 7.51 (m, 2H), 7.43 (ddd, J = 7.3, 5.0, 1.3 Hz, 1H), 6.98 (dd, J = 8.0 , 2.2 Hz, 1H), 4.02 (s, 3H), 3.03 (s, 6H); LRMS (M+H) m/z 399.64.

Example 62

N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(3-(methylsulfonamido)phenyl)picolinamide (I-60)

0.08 mmol scale, with (3-(methylsulfonamido)phenyl)boronic acid, 21.7 mg, 41% yield. 1H NMR (300 MHz, DMSO-afe) δ 12.64 (s, 1H), 9.99 (s, 1H), 8.72 (ddd, J = 5.0, 1.7, 0.9 Hz, 1H), 8.58 (s, 1H), 8.26-8.21 (m, 4H), 8.07 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 8 .03 (dd, J = 1.8, 1.8 Hz, 1H), 7.97 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.72 (dd, J = 7.9, 7.9 Hz, 1H), 7.49 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 7.42 (ddd, J = 7.4, 5 0, 1.3Hz, 1H), 4.02 (s, 3H), 3.11 (s, 3H); LRMS (M+H) m/z 449.45.

Example 63

6-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)-3',6'-dihydro-[2,4'-bipyridin]-1'(2 'H)-tert-butyl carboxylate (I-61)

0.15 mmol scale, with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate, 33 0.1mg, 48% yield. 1H NMR (300 MHz, Chloroform-d) 512.40 (s, 1H), 8.60 (ddd, J = 5.0, 1.8, 0.9 Hz, 1H), 8.49 (s, 1 H), 8.15 (dd, J = 7.7, 0.9 Hz, 1H), 8.10 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 7.86 (dd, J = 7.8, 7.8 Hz, 1H), 7.76 (ddd, J = 8,1,7.5, 1.8 Hz, 1H), 7.58 (d, J = 7 .8 Hz, 1H), 7.22 (ddd, J = 7.5, 5.0, 1.2 Hz, 1H), 6.93 (sa, 1H), 4.26 (sa, 2H), 3 .99 (s, 3H), 3.78 (t, J =5.6 Hz, 2H), 2.90 (bs, 2H), 1.53 (s, 9H); LRMS (M+H) m/z 461.80.

Example 64

N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-1',2',3',6'tetrahydro-[2,4'-bipyridin]-6 -carboxamide (I-62)

1H NMR (300 MHz, Chloroform-a) 512.41 (s, 1H), 8.59 (ddd, J = 5.0, 1.8, 0.9 Hz, 1H), 8.48 (s, 1H ), 8.12 (dd, J = 7.7, 0.9 Hz, 1H), 8.09 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 7.83 (dd, J = 7.8, 7.8z Hz, 1H), 7.75 (ddd, J = 8.0, 7.6, 1.8Hz, 1H), 7.55 (dd, J = 8.0, 0.9 Hz, 1 H), 7.20 (ddd, J = 7.5, 5.0, 1.2 Hz, 1 H), 7.04 - 7.00 (m, 1 H), 3.98 (s, 3H), 3.73 - 3.70 (m, 2H), 3.25 (t, J = 5.7 Hz, 2H), 2.83 - 2.79 (m , 2H), 2.06 (s, 1H); LRMS (M+H) m/z 361.48.

Example 65

N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(piperidin-4-yl)picolinamide (I-63)

1H NMR (300 MHz, Chloroform-a) 512.46 (s, 1H), 8.60 (ddd, J = 5.0, 1.7, 0.9 Hz, 1H), 8.45 (s, 1H ), 8.17 (dd, J = 7.7, 0.7 Hz, 1H), 8.08 (ddd, J = 8.1, 1.0, 1.0 Hz, 1H), 7.88 (dd, J = 7.8, 7.8 Hz, 1H), 7.75 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.29 - 7.25 (m, partially overlapped with chloroform, 1H), 3.98 (s, 3H), 3.70 (dt, J = 12.8, 3.0 Hz, 2H), 3.24-3.15 (m, 3H), 2.52-2.32 (m, 4H); LRMS (M+H) m/z 363.63.

Example 66

6-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)-5',6'-dihydro-[2,3'-bipyridin]-1'(2 'H)-tert-butyl carboxylate (I-64)

Example 67

N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-1',2',5',6'-tetrahydro-[2,3'-bipyridin]- 6-carboxamide (I-65) Example 68

(£)-3-(dimethylamino)-1 -(5-methoxypyridin-2-yl)prop-2-en-1-one

A 1,1-dimethoxy-N,N-dimethylmethanamine (1.4 mL, 10 mmol) solution of 1-(5-methoxypyridin-2-yl)ethane-1-one (755.8 mg, 5 mmol) was stirred at 110°C. After 16 hours, the reaction was complete, monitored by LC-MS. The solvent was removed in vacuo, the title compound was obtained as a brown solid: 1H NMR (300 MHz, Chloroform-a) 58.30 (dd, J = 2.9, 0.6 Hz, 1H), 8 .15 (dd, J = 8.7, 0.6 Hz, 1 H), 7.87 (d, J = 12.7 Hz, 1 H), 7.28 - 7.24 (m, partially overlapped with CHCh, 1H), 6.42 (d, J =12.7 Hz, 1H), 3.90 (s, 3H), 3.16 (bs, 3H), 2.95 (bs, 3H); LRMS (M+H) m/z 207.37.

Example 69

5-methoxy-2-(1H-pyrazol-3-yl)pyridine

An EtOH (5 mL) solution of (E)-3-(dimethylamino)-1 -(5-methoxypyridin-2-yl)prop-2-en-1-one (ca. 5 mmol) and hydrazine hydrate ( 0.32 mL, 6.5 mmol) was stirred at 85°C for 2 hours. The reaction was complete as monitored by LC-MS. After cooling to room temperature, H2O (ca. 10 mL) was added, and most of the organic solvent was removed in vacuo. The mixture was extracted with EtOAc (15 mL x 2), the organic layers combined, washed with H2O, dried ( _Na2SO4 ), filtered, and the solvent removed in vacuo _. The title compound was obtained as a brown solid: 801.5 mg (91% yield in 2 steps): 1 H NMR (300 MHz, Chloroformoa) 5 10.89 (vsa, 1H), 8.31 (dd, J = 3.0, 0.7 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.7, 3.0 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 3.90 (s, 3H); LRMS (M+H) m/z 176.30.

Example 70

5-methoxy-2-(1-methyl-1H-pyrazol-3-yl)pyridine

In an ice bath, to a THF (20 mL) solution of 5-methoxy-2-(1H-pyrazol-3-yl)pyridine (801 mg, 4.58 mmol), NaH (60% dispersion) was added. % in mineral oil, 274.5 mg, 6.87 mmol) portionwise. The reaction was held at 0°C for 30 minutes, then allowed to warm to room temperature over 20 minutes. After re-cooling to 0°C, Mel (0.3 mL, 4.81 mmol) was added dropwise. The reaction was then allowed to warm to room temperature, then warmed to 50°C overnight. By LC-MS, the reaction was complete. The reaction was cooled to room temperature, quenched with saturated aqueous NH4Cl (ca. 50 mL). Most of the THF was removed by rotary evaporation, and the mixture was extracted with EtOAc (50 mL x 2). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered, the solvent removed in vacuo. The title compound was obtained as a brown oil (contains mineral oil): 1H NMR (300 MHz, Chloroform-a) 5 8.32 (dd, J = 3.0, 0.7 Hz, 1H), 7.84 (dd, J = 8.7, 0.7 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 8.7, 3.0 Hz, 1H), 6.77 (d, J =2.3 Hz, 1H), 3.96 (s, 3H), 3.89 (s, 3H); LRMS (M+H) m/z 190.35.

Example 71

5-methoxy-2-(1-methyl-4-nitro-1H-pyrazol-3-yl)pyridine

On an ice bath, to a _H2SO4 (5 mL) solution of 5-methoxy-2-(1-methyl-1H-pyrazol-3-yl)pyridine (ca. 4.58 mmol), was added dropwise to drop HNO ₃ (90% aq. solution, 0.252 mL). After the addition, the reaction was allowed to warm to room temperature. After 17 hours, the reaction was quenched by pouring it onto ice, then made basic with solid NaOH and Na ₂ CO ₃ to about pH = 8. The precipitate was collected by filtration (removed unreacted starting material (SM) and desired product <about 1:1>, not separating on silica column), and further purified by silica gel chromatography to remove di-nitro by-product. The title compound was obtained as a tan solid: 663.2 mg (62% yield over 2 steps); 1H NMR (300 MHz, Chloroform-d) 58.43 (dd, J = 3.0, 0.7 Hz, 1H), 8.23 (d, J = 0.5 Hz, 1H), 7.75 ( dd, J = 8.7, 0.6 Hz, 1H), 7.29 (dd, J = 8.7, 3.0 Hz, 1H), 4.01 (s, 3H), 3.92 (s , 3H); LRMS (M+H) m/z 235.42. The structure was confirmed, in terms of regioselectivity, by the 1D-NOE experiment: NOE was observed between the methyl group and the proton in the pyrazole. The other regioisomer was also isolated:

5-methoxy-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridine

1H NMR (300 MHz, Chloroform-d) 58.24 (d, J = 0.4 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 4.04 (s, 3H), 4.03 (d, J = 0.4 Hz, 2H).

Example 72

3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-amine dihydrochloride

An EtOAc (20 mL) solution of 5-methoxy-2-(1-methyl-4-nitro-1H-pyrazol-3-yl)pyridine (663 mg, 2.83 mmol) and Pd-C (10% in C, 50% wet, 100 mg), was shaken in a Parr flask under 30 psi of hydrogen. After 21 hours, the reaction was complete as monitored by LC-MS. The solid was filtered off through a celite pad, washed with EtOAc and MeOH, and the filtrate collected in a flask with 4M HCl-dioxane solution (1.5 mL). A precipitate formed, and was collected by filtration, washing with EtOAc, and dried further in vacuo. The title compound was obtained as di-HCl salt: 703.8 mg (90% yield); 1H NMR (300 MHz, DMSO-afe) or 10.06 (bs, 2H), 8.37 (dd, J = 3.0, 0.7 Hz, 1H), 8.04 (d, J = 3, 7 Hz, 1H), 7.94 (dd, J = 8.8, 0.7 Hz, 1H), 7.60 (dd, J = 8.8, 3.0 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.64 (bs, 2H); LRMS (M+H) m/z 205.32.

Example 73

6-Bromo-N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)picolinamide (I-66)

0.8 mmol scale, with 6-bromopicolinic acid, 239.9 mg, 77% yield. 1H NMR (300 MHz, Chloroformod) δ 12.98 (s, 1H), 8.56 (dd, J = 3.0, 0.7 Hz, 1H), 8.33 (s, 1H), 8.20 (dd, J = 7.5, 1.0 Hz, 1H), 7.98 (dd, J = 8.8, 0.7 Hz, 1H), 7.75 (dd, J = 7.9, 7 .5 Hz, 1H), 7.65 (dd, J = 7.9, 1.0 Hz, 1H), 7.32 (dd, J = 8.8, 3.0 Hz, 1H), 3, 96 (s, 3H), 3.94 (s, 3H); LRMS (M+H) m/z 390.60.

Example 74

N-(3-(5-methoxypyridin-2-yl)-1 -methyl-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-5-yl)picolinamide (I-67)

0.08 mmol scale, 22.3 mg, 71% yield. 1H NMR (300 MHz, DMSO-afe) 5 13.29 (s, 1H), 12.40 (s, 1H), 8.52 (s, 1H), 8.46 (d, J = 2.4 Hz , 1H), 8.23 (dd, J = 6.8, 2.0 Hz, 1H), 8.15 - 8.08 (m, 3H), 8.01 (d, J = 8.8 Hz , 1H), 7.59 (dd, J = 8.9, 2.9 Hz, 1H), 7.20 (sa, 1H), 3.98 (s, 3H), 3.95 (s, 3H ); LRMS (M+H) m/z 376.61.

Example 75

N-(3-(5-methoxypyridin-2-yl)-1 -methyl-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide (I-68)

0.08 mmol scale, 11.1 mg, 37% yield.1H NMR (300 MHz, DMSO-afe) 13.34 (s, 1H), 12.32 (s, 1H), 8.55 ( s, 1H), 8.53 (s, 1H), 8.43 (d, J = 2.6 Hz, 1H), 8.37 (s, 1H), 8.19 - 7.96 ( m, 4H), 7.62 (dd, J =8.9, 3.0 Hz, 1H), 3.98 (s, 3H), 3.97 (s, 3H); LRMS (M+H) m/z 376.60.

Example 76

N-(3-(5-methoxypyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridine]-6-carboxamide (I-69 )

0.08 mmol scale, 28.2 mg, 88% yield.^ NMR (300 MHz, DMSO-afe) δ 12.48 (s, 1H), 9.53 (s, 1H), 8.59 (dd, J = 2.0, 0.7 Hz, 1H), 8.49 (dd, J = 2.9 Hz, 1H), 8.48 (s, 1H), 8.39 (ddd, J = 2,1,2,1,0.7 Hz, 1H), 8.30 (dd, J = 7.4, 1.6 Hz, 1H), 8.21 - 8.12 (m, 2H), 7.97 (dd, J = 8.9, 0.5 Hz, 1H), 7.55 (dd, J = 8.9, 3.0 Hz, 1H), 3.93 (s, 3H), 3 .91 (s, 3H), 2.44 (s, 3H); LRMS (M+H) m/z 401.66.

Example 77

5'-Isopropoxy-N-(3-(5-methoxypyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-70 ) 0.08 mmol scale, 24.1 mg, 68% yield. 1H NMR (300 MHz, DMSO-afe) 512.41 (s, 1H), 9.31 (d, J = 1.8 Hz , 1H), 8.57 (ad, J = 2.9 Hz, 1H), 8.49 - 8.48 (m, 2H), 8.37 (dd, J = 7.0, 2.0 Hz, 1H), 8.21 - 8.13 (m, 3H), 7.98 (dd, J = 8.9, 0.5 Hz, 1H), 7.56 (dd, J = 8.9, 3 .0 Hz, 1H), 4.92 (hept, J = 6.0 Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 1.38 (d, J = 6 .0Hz, 6H); LRMS (M+H) m/z 445.73.

Example 78

5'-(isopropylamino)-N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I- 71) ¹ H NMR (300 MHz, DMSO-ds) δ 12.60 (s, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.54-8.53 (m, 2H), 8.27 - 8.16 (m, 4H), 8.01 (d, J = 8.8 Hz, 1H), 7.63 - 7.62 (m, 1H), 7.59 (dd, J = 8.9, 3.0 Hz, 1H), 5.95 (d, J = 8.2 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.83 - 3.72 (m, 1H), 1.21 (d, J =6.3Hz, 6H); LRMS (M+H) m/z 444.80.

Example 79

4-nitro-3-(pyrrolidin-1 -yl)-1 H-pyrazole

A BuOH (5 mL) solution of 5-chloro-4-nitro-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.39 g, 5 mmol) and pyrrolidine (0.575 mL, 7 mmol) was stirred at 120°C for 15 hours, after which LC-MS indicated the reaction was complete. The volatiles were removed in vacuo, and the crude reaction mixture was treated with EtOH (10 mL) and 6N HCl (aq, 3 mL), and stirred at 70°C for 3 hours. Volatiles were removed in vacuo. After trituration with EtOH-EtOAc, the title compound was obtained as an orange solid: 631 mg as HCl salt; ; 1H NMR (300 MHz, DMSO-afe) 58.09 (s, 1H), 3.49-3.45 (m, 4H), 1.97-1.92 (m, 4H); LRMS (M+H) m/z 183.24. Example 80

1-(4-nitro-1H-pyrazol-3-yl)

5 mmol scale, with piperidine, 667.1 mg. . 1H NMR (300 MHz, DMSO-ds) 8.40 (s, 1H), 3.25-3.21 (m, 4H), 1.70-1.60 (m, 6H); LRMS (M+H) m/z 197.33.

Example 81

4-(4-nitro-1H-pyrazol-3-yl)morpholine

5 mmol scale, with morpholine, 540 mg. 1H NMR (300 MHz, DMSO-ds) 58.58 (s, 1H), 3.78-3.75 (m, 4H), 3.27-3.23 (m, 4H); LRMS (M+H) m/z 199.26.

Example 82

1-methyl-4-nitro-3-(pyrrolidin-1-yl)-1H-pyrazole

397.2 mg, 40% yield in 3 steps. 1H NMR (300 MHz, Chloroform-d) 58.03 (s, 1H), 3.76 (s, 3H), 3.38-3.33 (m, 4H), 2.08-2.04 (m , 4H); LRMS (M+H) m/z 197.34. The structure was confirmed by 1D-NOE experiment: NOE was observed between the protons of the methyl group and the proton of the pyrazole.

Example 83

1-methyl-3-(pyrrolidin-1-yl)-1H-pyrazol-4-amine

0.34 g as the 2-HCl salt. 1H NMR (300 MHz, Chloroform-d) 57.98 (c, J = 0.6 Hz, 1H), 3.76 (d, J = 0.5 Hz, 3H), 3.48 - 3.43 ( m, 4H), 1.96-1.91 (m, 4H); LRMS (M+H) m/z 167.28.

Example 84

1-(1-methyl-4-nitro-1H-pyrazol-3-yl)piperidine

460.1 mg, 44% yield over 3 steps. 1H NMR (300 MHz, Chloroform-a) 58.04 (d, J = 0.6 Hz, 1H), 3.78 (d, J = 0.5 Hz, 4H), 3.22-3.19 ( m, 4H), 1.75-1.68 (m, 4H), 1.64-1.56 (m, 2H); LRMS (M+H) m/z 211.36. The structure was confirmed by 1D-NOE experiment: NOE was observed between the protons of the methyl group and the proton of the pyrazole. The other regioisomer was also isolated and characterized:

1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine

1H NMR (300 MHz, Chloroform-d) 58.01 (s, 1H), 3.75 (s, 3H), 3.16-3.13 (m, 4H), 1.73-1.67 ( m, 6H).

Example 85

1-methyl-3-(piperidin-1-yl)-1H-pyrazol-4-amine dih hydrochloride

317.1 mg, as 2HCl salt, 91% yield 1H NMR (300 MHz, DMSO-d6) 59.75 (bs, 2H), 7.74 (s, 1H), 3.73 (s, 3H) , 3.66 (s, 2H), 3.02-2.98 (m, 4H), 1.69-1.61 (m, 4H), 1.58-1.52 (m, 2H); LRMS (M+H) m/z 181.38.

Example 86

4-(1-methyl-4-nitro-1H-pyrazol-3-yl)morpholine

337 mg, 37% yield in 3 steps. 1H NMR (300 MHz, Chloroform-d) 58.07 (d, J = 0.5 Hz, 1H), 3.88 - 3.85 (m, 4H), 3.81 (d, J = 0.5 Hz, 3H), 3.32-3.29 (m, 4H); LRMS (M+H) m/z 213.34. The structure was confirmed by 1D-NOE experiment: NOE was observed between the protons of the methyl group and the proton of the pyrazole.

Example 87

1 -methyl-3-morpholino-1H-pyrazol-4-amine

328.7 mg, as 2HCl salt, 81% yield 1H NMR (300 MHz, DMSO-afe) 510.00 (bs, 2H), 7.80 (d, J =0.9 Hz, 1H), 5 .31 (bs, 2H), 3.75-3.72 (m, 7H), 3.05-3.02 (m, 4H); LRMS (M+H) m/z 183.30.

Example 88

N-(1-methyl-3-(pyrrolidin-1-yl)-1H-pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide (I-72)

0.08 mmol scale, 20.7 mg, 77% yield. 1H NMR (300 MHz, Chloroform-d) 10.47 (bs, 1H), 9.85 (s, 1H), 8.14 (s, 2H), 8.09 (dd, J = 7.8, 1.0 Hz, 1H), 7.95 (s, 1H), 7.88 (dd, J = 7.8, 7.8 Hz, 1H), 7.65 (dd, J = 7.8, 1 0.0 Hz, 1H), 3.78 (s, 3H), 3.49-3.45 (m, 4H), 2.02-1.97 (m, 4H); LRMS (M+H) m/z 338.60.

Example 89

N-(1-methyl-3-(piperidin-1-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide (I-73)

0.08 mmol scale, 13.1 mg, 47% yield. 1H NMR (300 MHz, Chloroform-d) 10.52 (bs, 1H), 9.82 (s, 1H), 8.20 (s, 2H), 8.09 (dd, J = 7.8, 1.0 Hz, 1H), 8.05 (s, 1H), 7.88 (dd, J = 7.8, 7.8 Hz, 1H), 7.65 (dd, J = 7.8, 1.0 Hz, 1h), 3.81 (s, 3H), 3.12 - 3.09 (m, 4H), 1.83 - 1.75 (m, 4H), 1.66 - 1, 59 (m, partially overlapped with H2O, 2H); LRMS (M+H) m/z 352.52.

Example 90

N-(1-methyl-3-morpholino-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide (I-74)

0.08 mmol scale, 22 mg, 78% yield. 1H NMR (300 MHz, Chloroform-d) 510.61 (bs, 1H), 9.81 (s, 1H), 8.18 (s, 2H), 8.09 (dd, J = 7.8, 1 .0 Hz, 1H), 8.04 (s, 1H), 7.89 (d, J = 7.8, 7.8 Hz, 1H), 7.67 (dd, J = 7.9, 1 0.0 Hz, 1H), 3.94-3.91 (m, 4H), 3.82 (s, 3H), 3.18-3.15 (m, 4H); LRMS (M+H) m/z 354.53.

Example 91

5'-methyl-N-(1-methyl-3-(pyrrolidin-1-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-75)

0.08 mmol scale, 19.6 mg, 68% yield. 1H NMR (300 MHz, Chloroform-a) 59.90 (s, 1H), 9.04 (d, J = 2.1 Hz, 1H), 8.55 (dd, J = 2.1.0, 7 Hz, 1H), 8.25 (dd, J = 7.6, 1.1 Hz, 1H), 8.15 - 8.13 (m, 1H), 8.03 - 7.98 (m, 2H ), 7.92 (dd, J = 7.9, 1.1 Hz, 1H), 3.78 (s, 3H), 3.49 - 3.45 (m, 4H), 2.47 (s, 3H), 2.02-1.98 (m, 4H); LRMS (M+H) m/z 363.66.

Example 92

5'-methyl-N-(1-methyl-3-(piperidin-1-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-76)

0.08 mmol scale, 14 mg, 46% yield. 1H NMR (300 MHz, Chloroform-a) 59.87 (s, 1H), 9.07 (d, J = 1.9 Hz, 1H), 8.57-8.56 (m, 1H), 8 .27 - 8.24 (m, 2H), 8.05 (s, 1H), 8.04 - 7.98 (m, 1H), 7.94 (dd, J = 7.9, 1.2 Hz, 1H), 3.82 (s, 3H), 3.11 - 3.08 (m, 5H), 2.48 (s, 3H), 1.83 - 1.75 (m, 4H), 1.66-1.59 (m, partially overlapped with HzO, 5H); LRMS (M+H) m/z 377.71.

Example 93

5'-methyl-N-(1-methyl-3-morpholino-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-77)

0.08 mmol scale, 19.4 mg, 64% yield. .1H NMR (300 MHz, Chloroform-a) 59.86 (s, 1H), 9.06 (d, J = 2.1 Hz, 1H), 8.58 (dd, J = 2.1.0 0.7 Hz, 1H), 8.25 (dd, J = 7.5, 1.2 Hz, 1H), 8.21 - 8.19 (m, 1H), 8.04 - 7.99 (m, 2H), 7.94 (dd, J = 7.9, 1.2 Hz, 1H), 3.92 - 3.89 (m, 4H), 3.83 (s, 3H), 3.17 - 3.14 (m, 4H), 2.51 (bs, 3H); LRMS (M+H) m/z 379.69.

Example 94

6-(3-methyl-1 H-pyrazol-4-yl)-N-(1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide (I-78)

0.1 mmol scale, with 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl)-1H-pyrazole, 19.1 mg, 53% yield.

1H NMR (300 MHz, DMSO-afe) δ 12.98, 12.93 (s, s, two atropisomers, 1H), 12.25, 12.23 (s, s, two atropisomers 1H), 8.62 - 8.56 (m, 2H), 8.41.8.22 (s, s, two atropisomers, 1H), 8.10 - 8.05 (m, 2H), 8.00 - 7.93 (m, 2H), 7.87 - 7.83 (m, 1H), 7.45 - 7.40 (m, 1H), 4.01 (s, 3H), 2.66, 2.60 (s, s, two atropisomers, 3H); LRMS (M+H) m/z 360.68.

Example 95

2-(1 -isopropyl-1H-pyrazol-3-yl)pyridine

40 mmol scale, with 2-iodopropane, a light brown oil was used directly in the next reaction. 1H NMR (300 MHz, Chloroform-a) 58.62 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.94 (ddd, J = 8.0, 1.1, 1.1 Hz, 1H), 7.73 - 7.67 (m, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.17 (ddd, J = 7.5, 4 .9, 1.2 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 4.60 (hept, J = 6.7 Hz, 1H), 1.56 (d, J = 6.7Hz, 6H); LRMS (M+H) m/z 188.22.

Example 96

2-(1 -isopropyl-4-nitro-1H-pyrazol-3-yl)pyridine

40 mmol scale, after silica gel chromatography, a yellow solid: 8.79 g, 95% yield in 2 steps.

1H NMR (300 MHz, Chloroform-a) 58.75 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H), 8.29 (s, 1H), 7.84-7.72 (m, 2H), 7.36 (ddd, J = 7.4, 4.9, 1.4 Hz, 1H), 4.62 (hept, J = 6.7 Hz, 1H), 1.61 (d, J =6.7Hz, 6H); LRMS (M+H) m/z 233.28.

Example 97

1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-amine, dihydrochloride

Obtained as di-HCl salt, a light yellow solid: 9.99 g (96% yield); 1H NMR (300 MHz, Chloroform- d) 58.52 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 7.97 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 7.66 (ddd, J = 8,1,7.5, 1.8 Hz, 1H), 7.09 - 7.05 (m, 2H), 4.43 (hept , J = 6.7 Hz, 1H), 4.07 (sa, 2H), 1.49 (d, J = 6.7 Hz, 6H); LRMS (M+H) m/z 203.28.

Example 98

6-bromo-N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (I-79)

1.0 mmol scale, with 6-bromopicolinic acid, 244.7 mg, 63% yield. 1H NMR (300 MHz, Chloroform- d) 13.11 (s, 1H), 8.84 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.41 (s, 1H), 8.20 (dd, J = 7.5, 1.0 Hz, 1H), 8.07 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.65 (dd, J = 7.9, 1.0 Hz, 1H), 7.22 ( ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 4.56 (hept, J = 6.7 Hz, 1H), 1.58 (d, J = 6.7 Hz, 6H); LRMS (M+H) m/z 386.58, 388.49.

Example 99

N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide (I-80)

0.1 mmol scale, 32 mg, 86% yield.1H NMR (300 MHz, DMSO-de) 13.31 (s, 1H), 12.38 (s, 1H), 8.76 (ddd, J = 5.0, 1.7, 0.9 Hz, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 8.36 - 8.35 (m, 1H), 8 .13 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 8.08 (dd, J = 8.0, 7.3 Hz, 1H), 8.02 - 7, 96 (m, 3H), 7.47 (ddd, J = 7.4, 5.0, 1.3 Hz, 1H), 4.69 (hept, J = 6.7 Hz, 1H), 1.55 (d, J =6.7Hz, 6H); LRMS (M+H) m/z 374.69.

Example 100

N-(1-isopropyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridine]-6-carboxamide (I-81)

0.1 mmol scale, 31.4 mg, 79% yield. 1H NMR (300 MHz, DMSO-afe) 512.63 (s, 1H), 9.55 (d, J = 2.1 Hz, 1H), 8.81 (ddd, J = 5.0, 1.7 , 0.9 Hz, 1H), 8.67 - 8.66 (m, 1H), 8.61 (s, 1H), 8.48 (ddd, J = 2.1,2,1.0, 7 Hz, 1H), 8.38 (dd, J = 7.4, 1.6 Hz, 1H), 8.28 - 8.19 (m, 2H), 8.12 (ddd, J = 8, 1, 1.1, 1.1 Hz, 1H), 8.01 - 7.95 (m, 1H), 7.47 (ddd, J = 7.4, 5.0, 1.2 Hz, 1H ), 4.69 (hept, J = 6.7 Hz, 1H), 2.51 (s, 3H), 1.56 (d, J = 6.7 Hz, 6H); LRMS (M+H) m/z 399.69. Example 101

4-(2-(3-(pyridin-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine

15 mmol scale, with 4-(2-bromoethyl)morpholine hydrobromide, a light orange-brown oil was used directly in the next reaction. 1H NMR (300 MHz, Chloroform-d) 58.63 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.90 (ddd, J = 8.0, 1.1, 1.1 Hz, 1H), 7.70 (ddd, J = 8.0, 7.5, 1.8 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.19 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 4.32 (t, J = 6, 6 Hz, 2H), 3.72-3.68 (m, 4H), 2.87 (t, J =6.6 Hz, 2H), 2.51-2.48 (m, 4H); LRMS (M+H) m/z 259.53.

Example 102

4-(2-(4-nitro-3-(pyridin-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine

15 mmol scale, 3.145 mg, 69% yield. .1H NMR (300 MHz, Chloroform-d) 58.75 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H), 8.41 (s, 1H), 7.81 (ddd, J = 7.9, 7.2, 1.7 Hz, 1H), 7.76 (ddd, J = 7.9, 1.6, 1.0 Hz, 1H), 7.37 (ddd, J = 7.2, 4.9, 1.6 Hz, 1H), 4.32 - 4.30 (m, 2H), 3.74 - 3.71 (m, 4H), 2.89 - 2.85 ( m, 2H), 2.54-2.51 (m, 4H); LRMS (M+H) m/z 304.56. A mixed fraction (1.17 g) was obtained with about 26% of the other regioisomer. The structure of the title compound was confirmed by 1D-NOE experiment: NOE was observed between CH ₂ protons connecting to the pyrazole nitrogen and the proton in the pyrazole.

Example 103

1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-amine trihydrochloride

10.35 mmol scale, obtained as the trihydrochloride salt: 2.92 g (74% yield); 1H NMR (300 MHz, DMSO-ofe) 511.55 (s, 1H), 10.26 (sa, 2H), 8.70 (ddd, J = 4.9, 1.3, 1.3 Hz, 1H ), 8.28 (s, 1H), 8.04 - 7.97 (m, 2H), 7.49 (ddd, J = 5,1,5,1,3.5 Hz, 1H), 5, 20 (sa, 3H), 4.80 (t, J = 6.7 Hz, 2H), 3.98-3.88 (m, 4H), 3.70 (t, J = 6.7 Hz, 2H ), 3.49-3.40 (m, 2H), 3.25-3.17 (m, 2H); LRMS (M+H) m/z 274.54.

Example 104

6-Bromo-N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (I-82)

1.0 mmol scale, 323.6 g, 71% yield. 1H NMR (300 MHz, Chloroform-d) 13.05 (s, 1H), 8.86 (brd, J = 4.7 Hz, 1H), 8.50 (s, 1H), 8.21 ( d, J = 7.4 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.66 (d, J = 7 .9 Hz, 1H), 7.30 - 7.26 (m, 1H, partially overlapped with CHCh), 4.77 - 4.70 (m, 2H), 4.03 - 3.94 (m, 4H) , 3.54-3.44 (m, 2H), 3.02-2.84 (m, 4H); LRMS (M+H) m/z 457,61,459.50.

Example 105

N-(1 -(2-morpholinoethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide (I-83)

0.1 mmol scale, 27.8 mg, 63% yield. 1H NMR (300 MHz, Chloroform-d) 512.56 (s, 1H), 10.35 (vsa, 1H), 8.73 (ddd, J = 5.0, 1.8, 0.9 Hz, 1H ), 8.56 (s, 1H), 8.33 (s, 2H), 8.13 - 8.09 (m, 2H), 7.88 (dd, J = 7.8, 7.8 Hz, 1H), 7.76 (ddd, J = 8,1,7.5, 1.8 Hz, 1H), 7.65 (dd, J = 7.8, 1.0 Hz, 1H), 7.23 (ddd, J = 7.5, 5.0, 1.1 Hz, 1H), 4.32 (t, J = 6.8 Hz, 2H), 3.74 - 3.71 (m, 4H), 2.92 (t, J =6.8 Hz, 2H), 2.55-2.52 (m, 4H); LRMS (M+H) m/z 445.79.

Example 106

5'-methyl-N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I -84)

0.1 mmol scale, 27.9 g, 59% yield. 1H NMR (300 MHz, Chloroform-d) 512.83 (s, 1H), 9.38 (ad, J = 2.1 Hz, 1H), 8.74 (ddd, J = 5.0, 1, 8, 1.0 Hz, 1H), 8.61 (dd, J = 2.1,0.7 Hz, 1H), 8.55 (s, 1H), 8.29-8.26 (m, 2H), 8.10 (ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 8.04 - 7.99 (m, 1H), 7.93 (dd, J = 7, 9, 1.2 Hz, 1H), 7.76 (ddd, J = 8,1,7,5, 1.8 Hz, 1H), 7.26 -7.22 (m, 1H, partially overlapped with CHCh ), 4.32 (s, J = 6.8 Hz, 2H), 3.74 - 3.71 (m, 4H), 2.92 (t, J = 6.8 Hz, 2H), 2.55 - 2.52 (m, 4H), 2.51 (bs, 3H); LRMS (M+H) m/z 470.85.

Example 107

1-methyl-4-(2-(4-nitro-3-(pyridin-2-yl)-1H-pyrazol-1-yl)ethyl)piperazine

10 mmol scale, 1s stage: crude was used directly in the next reaction; 2nd stage: after chromatography on silica gel, 1.69 g, 53% yield. 1H NMR (300 MHz, Chloroform-d) 58.75 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H), 8.42 (s, 1H), 7.84-7.74 (m, 2H), 7.37 (ddd, J = 7,1,4,9, 1.6 Hz, 1H), 4.33 - 4.29 (m, 2H), 2.89 - 2, 85 (m, 2H), 2.60 -2.39 (m, 8H), 2.31 (s, 3H); LRMS (M+H) m/z 317.63.

Example 108

1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-amine trihydrochloride 5.3 mmol scale, obtained as the trihydrochloride salt : 1.67 g, 79% yield; LRMS (M+H) m/z 287.55.

Example 109

6-Bromo-N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide (I-85)

1.0 mmol scale, 342.1 g, 73% yield. 1H NMR (300 MHz, Chloroform-d) 13.10 (s, 1H), 8.85 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H), 8.40 (s, 1H), 8.19 (dd, J = 7.5, 0.9 Hz, 1H), 8.03 (ddd, J = 8.1, 1.0, 1.0 Hz, 1H), 7.78 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H), 7.77 (dd, J = 7.7, 7.7 Hz, 1H), 7.67 (dd, J = 7 .9, 0.9 Hz, 1H), 7.28 - 7.24 (m, partially overlapped with CHCh, 1H), 4.27 (t, J = 5.9 Hz, 2H), 3.39 - 3.29 (m, 2H), 3.01 (t, J =5.9 Hz, 2H), 3.03-2.81 (m, 6H), 2.73 (s, 3H); LRMS (M+H) m/z 472.68.

Example 110

N-(1 -(2-(4-methylpiperazin-1 -yl)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4- il) picolinamide (I-86) 0.1 mmol scale, 15.2 mg, 33% yield. 1H NMR (300 MHz, DMSO-afe) 513.35 (sa, 1H), 12.38 (s, 1H), 8.76 (bd, J = 4.9 Hz, 1H), 8.63 (s , 1H), 8.46 (sa, 2H), 8.12 - 8.05 (m, 2H), 8.01 - 7.96 (m, 3H), 7.47 (ddd, J = 7, 4, 5.0, 1.0 Hz, 1H), 4.38 (t, J = 6.5 Hz, 2H), 3.44 (vsa, 2H), 2.85 (t, J = 6.5 Hz, 2H), 2.57-2.52 (m, overlapped with DMSO, 6H), 2.29 (s, 3H); LRMS (M+H) m/z 458.81.

Example 111

5'-methyl-N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'- bipyridine]-6-carboxamide (I-87)

0.1 mmol scale, 9.1 mg, 19% yield. 1H NMR (300 MHz, DMSO-afe) 512.61 (s, 1H), 9.54 (d, J = 1.8 Hz, 1H), 8.80 (d, J = 4.5 Hz, 1H) , 8.66 (d, J = 1.0 Hz, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 8.37 (dd, J = 7.1, 1 .8 Hz, 1H), 8.27 - 8.19 (m, 2H), 8.09 (ad, J = 8.0 Hz, 1H), 7.98 (ddd, J = 7.8, 7, 8, 1.7 Hz, 1H), 7.47 (ddd, J = 7.4, 5.0, 1.0 Hz, 1H), 4.39 (t, J = 6.5 Hz, 2H), 3.38 (vsa, 2H), 2.84 (t, J =6.5 Hz, 2H), 2.50 (s, 3H), 2.57-2.51 (m,overlapped with DMSO, 2H) , 2.42 (bs, 4H), 2.22 (s, 3H); LRMS (M+H) m/z 483.88.

Example 112

N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-oxo-1',2'-dihydro-[2,4'-bipyridin]-6 -carboxamide (I-91)

1H NMR (300 MHz, DMSO-afe) δ 12.48 (s, 1H), 11.72 (sa, 1H), 9.00 (ddd, J = 5.0, 1.7, 0.9 Hz, 1H), 8.59 (s, 1H), 8.35 (dd, J = 7.0, 2.0 Hz, 1H), 8.27 - 8.24 (m, 2H), 8.08 ( ddd, J = 8.1, 1.1, 1.1 Hz, 1H), 7.97 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.14 (dd, J = 6.9, 1.8 Hz, 1H), 6.34 (ddd, J = 9.2, 1.0, 1.0 Hz , 1H), 6.18 (ddd, J = 6.5, 6.5, 1.2 Hz, 1H), 4.01 (s, 3H); LRMS (M+H) m/z 373.60.

Example 113

N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-6 -carboxamide (I-92)

1H NMR (300 MHz, DMSO-afe) δ 12.39 (s, 1H), 12.30 (s, 1H), 8.73-8.70 (m, 1H), 8.57 (s, 1H) , 8.52 (dd, J = 9.6, 2.7 Hz, 1H), 8.41 (d, J = 2.9 Hz, 1H), 8.16 (dd, J = 7.6, 1 0.8 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 8.07 - 8.04 (m, 2H), 7.98 (ddd, J = 7.7, 7, 7, 1.7 Hz, 1H), 7.48 (ddd, J = 7.4, 5.0, 1.4 Hz, 1H), 6.70 (d, J = 9.6 Hz, 1H), 4.01 (s, 3H); LRMS (M+H) m/z 373.62.

Example 114

N-(3-(3,5-difluoropyridin-2-yl)-1 -(írans-4-ethoxycyclohexyl)-1 HLpyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide (I -184) 1H NMR (300 MHz, Chloroform-d) 512.17 (s, 1H), 8.58 (bs, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8 .26 (sa, 2H), 8.10 (dd, J = 7.7, 1.0 Hz, 1H), 7.88 (dd, J = 7.8, 7.8 Hz, 1H), 7 .65 (dd, J = 7.9, 1.1 Hz, 1H), 7.36 (ddd, J = 10.7, 8.3, 2.4 Hz, 1H), 4.28 (tt, J = 11.8, 3.8 Hz, 1H), 3.57 (c, J = 7.0 Hz, 2H), 3.38 (tt, J = 10.7, 4.1 Hz, 1H), 2 .33 - 2.20 (m, 4H), 1.97 - 1.84 (m, 2H), 1.55 - 1.41 (m, 2H), 1.23 (t, J = 7.0 Hz , 3H); LRMS (M+H) m/z 494.28.

Example 115

N- ( 1 -(írans-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide (I-205 )

1H NMR (400 MHz, Chloroform-d) δ 12.19 (s, 1H), 10.57 (sa, 1H), 9.38 (d, J = 1.5 Hz, 1H), 8.64 (dd , J = 2.7, 1.6 Hz, 1H), 8.53 (s, 1H), 8.48 (d, J = 2.6 Hz, 1H), 8.31 (s, 2H) , 8.09 (dd, J = 7.7, 1.0 Hz, 1 H), 7.88 (dd, J = 7.8, 7.8 Hz, 1 H), 7.65 (dd, J = 7.9, 1.0 Hz, 1H), 4.22 (tt, J = 11.8, 3.9 Hz, 1H), 3.57 (c, J = 7.0 Hz, 2H), 3 .38 (tt, J = 10.6, 4.1 Hz, 1H), 2.31 - 2.20 (m, 4H), 1.98 - 1.88 (m, 2H), 1.53 - 1 .43 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H); LRMS (M+H) m/z 459.3.

Example 116

N- ( 1 -(írans-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridine]-6-carboxamide (I-206) 1H NMR (400 MHz, Chloroform-d) δ 12.43 (s, 1H), 9.46 (dd, J = 2.2, 0.7 Hz, 1H), 9.37 (d , J = 1.5 Hz, 1H), 8.72 (dd, J = 2.7, 1.6 Hz, 1H), 8.60 (dd, J = 2.1,0.9 Hz, 1H) , 8.52 (s, 1H), 8.51 (d, J = 2.7 Hz, 1 H), 8.25 (dd, J = 7.6, 1.0 Hz, 1 H), 8, 15 (ddd, J = 2,1,2,1,0.9 Hz, 1H), 8.01 (dd, J = 7.8, 7.8 Hz, 1H), 7.92 (dd, J = 7.9, 1.0 Hz, 1H), 4.23 (tt, J = 11.8, 3.9 Hz, 1H), 3.57 (c, J = 7.0 Hz, 2H), 3, 38 (tt, J = 10.6, 4.1 Hz, 1H), 2.49 (bd, J = 0.7 Hz, 3H), 2.32-2.21 (m, 4H), 1.98 -1.88 (m, 2H), 1.53-1.43 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H); LRMS (M+H) m/z 484.3.

Example 117

N- ( 1 -methyl-3-(pyrazin-2-yl)-1 -W-pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide (I-207)

1H NMR (400 MHz, Chloroform-a) 512.19 (s, 1H), 9.39 (d, J = 1.6 Hz, 1H), 8.67 (dd, J = 2.7, 1.6 Hz, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.50 (s, 1H), 8.31 (s, 2H), 8.11 (dd, J = 7 .7, 1.0 Hz, 1H), 7.90 (t, J = 7.8 Hz, 1H), 7.66 (dd, J = 7.8, 1.0 Hz, 1H), 4, 02(s, 3H); LRMS (M+H) m/z 347.3.

Example 118

5'-methyl-N-(1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide (I-208)

1H NMR (400 MHz, Chloroform-a) 512.43 (s, 1H), 9.46 (d, J = 2.0 Hz, 1H), 9.37 (d, J = 1.5 Hz, 1H) , 8.74 (dd, J = 2.7, 1.6 Hz, 1H), 8.61 (dd, J = 2,1,0.9 Hz, 1H), 8.53 (d, J = 2 .6 Hz, 1H), 8.49 (s, 1H), 8.26 (dd, J = 7.6, 1.0 Hz, 1H), 8.16 (ddd, J = 2.1,2, 1, 0.9 Hz, 1H), 8.01 (dd, J = 7.8, 7.8 Hz, 1H), 7.93 (dd, J = 7.9, 1.0 Hz, 1H), 4.02 (s, 3H), 2.50 (c, J =0.7 Hz, 3H); LRMS (M+H) m/z 372.3.

Example 119

Preparation of 8-ethoxy-1,4-dioxaspiro[4.5]decane

Sodium hydride (60% dispersion in mineral oil, 74.3 g, 1.858 mol) in a round bottom flask was washed four times with hexanes. A suspension was made in THF (1 L) and cooled to 0 °C. Gradually, 1,4-dioxaspiro[4,5]decan-8-ol (150 g, 929 mmol) was added and the reaction was allowed to warm to room temperature. After two hours, the reaction was cooled back to 0 °C and iodoethane was added via a dropping funnel over one hour. The reaction was allowed to gradually warm to room temperature, after which a reflux condenser was installed. The reaction was monitored by TLC (1:1 ethyl acetate in hexanes). Upon completion, the reaction was quenched with ice, the solvent reduced by volume in vacuo, and then diluted with ethyl acetate and water. After extracting twice with ethyl acetate, the combined organic layers were washed with brine, dried over solid sodium sulfate, filtered, and concentrated in vacuo. After drying under high vacuum, 166.9 g of 8-ethoxy-1,4-dioxaspiro[4,5]decane were obtained as a yellow oil.

1H NMR (300 MHz, Chloroform-d) 53.90 (t, J = 2.2 Hz, 4H), 3.45 (c, J = 7.0 Hz, 2H), 3.40 - 3.32 ( m, 1H), 1.82-1.62 (m, 6H), 1.56-1.46 (m, 2H), 1.16 (t, J=7.0 Hz, 3H).

Example 120

Preparation of 4-ethoxycyclohexan-1-one

To a solution of 8-ethoxy-1,4-dioxaspiro[4,5]decane (166.9 g, 896.1 mmol) in THF (700 mL) was added a 3M aqueous HCl solution (597 mL). The solution was heated at 90 °C with an attached reflux condenser for two hours. The reaction was monitored by TLC (1:1 ethyl acetate in hexanes) by taking aliquots quenched with aqueous NaOH, and extracting into ethyl acetate. On completion, the volume of solvent was reduced in vacuo and adjusted to pH 8 with 4M NaOH solution. This was extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over solid sodium sulphate, filtered and concentrated in vacuo. After drying under high vacuum, 124.2 g of the desired 4-ethoxycyclohexan-1-one were obtained as a yellow oil.

¹ H NMR (300 MHz, Chloroform-d) 53.74 - 3.61 (m, 1H), 3.53 (c, J = 7.0 Hz, 2H), 2.63 - 2.46 (m, 2H), 2.30-2.15 (m, 2H), 2.12-1.82 (m, 4H), 1.21 (t, J =7.0 Hz, 3H).

Example 121

Preparation of (1s,4s)-4-ethoxycyclohexan-1-ol

A solution of 4-ethoxycyclohexan-1 -one (121.6 g, 855 mmol) in 750 mL THF was cooled to -78°C. Solid LiAlH4 (95%, 51.2 g, 1.28 mol) was added portionwise over one hour, then gradually warmed to -10°C. After one hour, an aliquot was taken, and quenched for analysis by TLC in 1:1 ethyl acetate in hexanes, which showed the reaction to be complete. The reaction was cooled back to -78 °C and quenched with the dropwise addition of 4 M NaOH solution (641 mL). The mixture was diluted and washed three times with ethyl acetate, decanting off the solvent. The combined organic phases were washed with 1M NaOH, brine, dried over solid sodium sulfate, filtered, and concentrated in vacuo. After drying under high vacuum, 117.9 g of 4-ethoxycyclohexan-1-ol (in ~2:1 ratio of 1s,4s and 2s,4s isomers) was obtained as a yellow oil.

1H NMR (300 MHz, Chloroform-d) 53.76 - 3.61 (m, 1H), 3.52 - 3.38 (m, 2H), 3.34 (dp, J = 6.3, 3 .2 Hz, 1H), 3.27 - 3.18 (m, ~0.5H), 2.01 - 1.92 (m, 1H), 1.84 - 1.47 (m, 6H), 1.33-1.25 (m, 1H), 1.17 (td, J=7.0, 2.5Hz, 3H).

Example 122

Preparation of 4-ethoxycyclohexyl (1r,4r)-4-nitrobenzenesulfonate

To a solution of 4-ethoxycyclohexan-1 -ol (~2:1 ratio of 1s,4s and 2s,4s isomers; 112.9 g, 782.9 mmol) in CH2G 2 (800 mL), cooled to 0°C, 1,4-diazabicyclo[2.2.2]octane (105.4 g, 939.5 mmol) was added. 4-Nitrobenzenesulfonyl chloride was added portionwise at 0°C over 1 hour and then the reaction gradually warmed to room temperature overnight. When the reaction appeared complete by TLC analysis in 1:1 ethyl acetate in hexanes, it was quenched with the addition of saturated aqueous NaHCO ₃ solution. After further dilution with CH ₂ G 2 and water, the organic phase was isolated and further washed with NaHCO ₃ solution, water and brine. After drying over solid sodium sulfate, the solution was filtered, concentrated in vacuo and dried under high vacuum. The resulting solid was triturated in ethyl acetate and hexanes to yield 160.8 g of 4-ethoxycyclohexyl 4-nitrobenzenesulfonate (as a mixture of 1r,4r and 1s,4s) as an off-white solid.

¹ H NMR (300 MHz, Chloroform-d) 58.51 - 8.31 (m, 2H), 8.17 - 8.03 (m, 2H), 4.73 (dtt, J = 11.7, 8 ,1,4.0 Hz, 1H), 3.44 (qd, J = 7.0, 1.5 Hz, 2H), 3.34 (tt, J = 6.7, 3.1 Hz, 1H) , 1.99-1.87 (m, 2H), 1.81-1.53 (m, 6H), 1.16 (td, J =7.0, 2.8 Hz, 3H).

Example 123

LPS-induced IL23p19 assay in THP-1 cells (with IFNy primed)

Materials and Equipment

THP-1 cells (ATCC, cat. no. TIB-202), dimethyl sulfoxide (DMSO) (Sigma-Aldrich, cat. no. D2650), RPMI 1640 (Cellgro, cat. no. 10-040 -CM), fetal bovine serum (Sigma, cat. no. F4135), bovine serum albumin (BSA) (Sigma-Aldrich, cat. no. A7906), LPS (serotype K-235, Sigma, product no. L 2143), IFNy (Peprotech, cat. no.

300-02)

Capture antibody: human IL-23p19 ELISA (e-Bioscience, Cat. no. 14-7238-85), Detection antibody: Biotinylated Primary Mouse anti-human IL-12 (p40/p70) (e-Bioscience, no. 13-7129-85), HRP-conjugated secondary streptavidin (R&D Systems, cat. no. DY998), 1x PBST wash buffer (PBS-Tween tablet) (VWR International, cat. no. 80058-558), ELISA blocking buffer (PBS with 1% BSA), ELISA dilution buffer (PBS with 1% BSA), MaxiSorp Black Immuno 384-well flat-bottom plates (Thermo Scientific, # 12-565-346), white 384-well flat-bottom tissue culture plates (Thermo Scientific, cat. no.

12-565-343), Super Signal ELISA Pico chemiluminescent substrate (Thermo Scientific, cat. no. 37070), Cell Titer Glo reagent (Promega, cat. no. G7573), positive control, IKK ₂ VI inhibitor (Calbiochem, cat. no. 401483), AquaMax 4000 plate washer (Molecular Devices), luminometer, Wallac Victor2 1420 Multilabel counter.

Method

Stim ulation of THP-1 Cells:

On day 1, 50K/well THP-1 cells were seeded and primed with IFNγ (50 ng/ml) in 384-well plates for approximately 18 hours in RPMI medium with 10% FBS. On day 2, the compound was serially diluted in 5 mM DMSO in 3-fold dilutions, and then diluted 1:125 in RPMI medium with 10% FBS. 50 µl/well of 2x compound was added to 50 µl/well of THP-1 cells (primed with IFNγ) in duplicate in 384-well tissue culture plates. Cells were preincubated with compound for 1 hour at 37°C, 5% COz before the addition of 10 µl/well 1x LPS to give a final concentration of 1 µg/ml LPS. On day 3, after stimulation for 18 hours at 37°C, 5% CO ₂ , the assay plate was centrifuged and 70 µl/well supernatant was collected. IL-23p19 protein in 70 µl/well of supernatant was measured by sandwich ELISA, and 25 µl/well of Cell Titer Glo reagent was added to the remaining cells to measure compound toxicity.

E L IS A sandwich type for human IL-23p19:

Maxisorp immuno ELISA plates were precoated with 25 µl/well of anti-IL-23p19 capture antibody (2.5 µg/ml) in PBS overnight at room temperature. After washing with 1x PBST, the plates were blocked using 100 µl/well 1% BSA in PBS for 2 hours at room temperature. The plates were washed three times with 1 x PBST, and 70 µl/well of supernatant was added. The plates were incubated at room temperature for 2 hours with shaking, and washed three times with 1x PBST. 25 µl/well of biotinylated anti-IL-12 (p40/p70) detection antibody (100 ng/ml) in PBS with 1% BSA was added and the plates were incubated at room temperature for 2 hours with shaking. After washing three times with 1x PBST, 25 µl/well streptavidin-HRP (1:200) in PBS with 1% BSA was added, and the plates were incubated at room temperature for 20 min with shaking. Plates were washed three times with 1x PBST, and 25 µl/well Super Signal ELISA Pico chemiluminescent substrate was added. Plates were read with a luminometer and chemiluminescence values were entered into Athena (Rigel) for curve fitting, EC50 calculation and storage in the database. The results are shown in Table 1.

Example 124

Detection of compounds by DC cells

Materials

Human PBMC cells (All cells, Cat # PB002)

RPMI growth medium containing 10% FBS

IFNy (Peprotech, Cat no. 300-02)

GMCSF (Peprotech, Cat #300-03) and IL4 (Peprotech Cat #200-04)

96-well white clear bottom plates (Fisher, Cat. No. 07-200-587, Corning #3903) LPS (make 2.5 mg/ml material in PBS) from Sigma Aldrich (Cat. No. L2018-5MG )

Cell Titer Glo Reagent (Promega, Cat No. G7573)

Positive controls, IKK ₂ VI inhibitor (Calbiochem, Cat no. 401483)

Protocol

I. Differentiation of PBMCs to DC cells:

Human PBMC cells (400 million) obtained from the supplier were transferred to a T-175 flask containing 15 mL RPMI medium (10% FBS) and incubated for 2 hours at 37°C. After 2 hours, the medium including floating cells was carefully aspirated and 12 ml of fresh RPMI medium (10% FBS) containing GMCSF (100 ng/ml) and IL4 (20 ng/ml) was added, and the flask it was kept in an incubator at 37 °C for 7 days. After 3 days, fresh GMCSF (100 ng/ml) and IL4 (20 ng/ml) were added to the flask and incubation continued. After 7 days, fully differentiated cells were collected by centrifugation (1200 rpm/5 min) and aspirating the medium. Cells were suspended in fresh RPMI medium (10% FBS) containing 50 ng/ml IFNγ (1000 U/ml) and then plated (50 K/well in 100 µL) on a clear-bottomed white plate. of 96 wells and left in an incubator at 37 °C for 24 hours.

II. Addition of compounds:

After 24 hours of incubation, 100 µL of RPMI medium containing 2X concentrated test compound per well was added to the above cell culture medium (final concentration becomes 1X), and plates were pre-incubated for 1 hour at 37°C. C before stimulating with LPS.

After 1 hour of compound preincubation, 10 µl per well of 20X concentrated LPS solution in RPMI medium was added, to give a final concentration of 1 µg/ml. The mixture was vortexed and the plates were incubated at 37°C for an additional 18 hours.

155 µL of the supernatant from each well was carefully collected (without the tip touching the bottom of the well) and 50 µL of Cell Titer Glo reagent was added to the remaining 50 µL/well of the cell culture plate. The mixture was incubated for 1-2 minutes on a shaker and the luminescence intensity of the plate was read to determine the cytotoxicity of the compound. The cell culture supernatant collected above was used to carry out IL23 ELISA (65 µl - Supernatant) and IL10 ELISA (90 µl - Supernatant) as described below.

Example 125

Human IL-23 (p19/p40) ELISA Protocol (e-Biosciences)

Materials:

96-well high-binding opaque white plates (from Pierce, Cat #15042);

1X PBS; TBST 1X washout buffer;

Blocking Solution: 0.5% Casein in PBS (from BDH, Cat #440203H);

Dilution Solution: 1% BSA in PBS (10% BSA from Fisher, Cat #37525);

Capture antibody: rat anti-human IL-23 (p19) (e-Biosciences, Cat. no. 14-7238-85);

Detection Antibody: Biotinylated Primary Mouse anti-human IL-12 (p40/p70) (e-bioscience, Cat n° 13-7129-85);

Secondary HRP-conjugated streptavidin (R&D Systems, Cat #DY998);

rHuman IL-23 (e-biosciences, Cat #34-8239) (suggested initial concentration = 5 ng/ml in RPMI cell culture medium);

Cell Culture Supernatant (65 ml of THP-1 cells primed with IFN ^and (50 ng/ml - 1000 U/ml) and stimulated with 0.01% SAC);

SuperSignal ELISA Pico Chemiluminescent Substrate [Pierce, Cat #37069].

Coating Plates:

To 10.5 ml of PBS was added 50 ml of anti-IL23 (p19) capture antibody (2.5 gg/ml). The mixture was mixed well and 100 ml of the coating solution was added to each well of Pierce 96-well white plates. Wells were covered and incubated overnight at 4°C.

Blocking of the plates:

Anti-IL23 (p19) antibody-coated plates were washed 2 times using TBST (use plate washer), and blocked using 200 ml 0.5% casein for 1.5-2 hours at room temperature with shaking. . Addition of Supernatant and Detection:

Plates were washed 2 times using TBST, and the supernatant was transferred (65 ml/well) to the preblocked/anti-IL23(p19) antibody-coated 96-well plate above, and incubated at room temperature for 1.5 hours. with agitation.

The plates were washed 4 times using TBST (plate washer), and 100 ml/well of detection antibody solution prepared from 2 ml of biotinylated anti-IL-12 (p40/p70) antibody was added in 11 mL of 1% BSA/PBS solution (1-5000 dilution). The plates were incubated for 1 hour with shaking at room temperature.

Again, the plates were washed 4 times with TBST, and 100 ml of HRP-labeled streptavidin solution (R&D Systems) (10 ml/10 ml of 1% BSA solution) was added, and the plates were incubated at room temperature. ambient for another 45 min with shaking.

After 45 min, the plates were washed with TBST 4 times, and 100 ml/well of Pierce's Super Signal ELISA Pico chemiluminescent substrate (3.5 ml A 3.5 ml B 3.5 ml MQ water) was added. The plates were shaken for 1-2 minutes and then read on a plate reader.

The EC ⁵⁰ results of the tests described in Examples 123 and 125 are shown in Table 1. Compounds 1-72 to 1-77 are reference compounds only, and do not form part of the invention.

V. Exemplary Embodiments of Compounds of the Invention, and Their Uses

The following numbered paragraphs illustrate exemplary embodiments of the compounds of the invention, and the purposes for which such compounds may be used.

Paragraph 1. A compound, having a formula 1

or a salt thereof, wherein:

ring A is heteroaryl;

R1 is H, or C _1-6 alkyl;

R2 is H, aliphatic, heteroaliphatic, or heterocyclyl;

each Z1, Z2, Z3, and Z4, is independently N or CR3, wherein at least one of Z1, Z2, Z3, and Z4 is N; each R3 is independently H, aliphatic, or heteroaliphatic; and

R4 is halogen, heteroaryl, heterocycloaliphatic, aryl, -NH-heteroaryl, or -O-heteroaryl.

Paragraph 2. [Omitted]

Paragraph 3. The compound of paragraph 1, wherein ring A is pyridinyl or pyrazinyl.

Paragraph 4. The compound of any one of paragraphs 1-3, wherein ring A is pyridin-2-yl.

Paragraph 5. The compound of any one of paragraphs 1-4, in which ring A is

each Q is independently CH or N, where at least one Q is N;

Rm is Rb;

x is 0, 1, or 2;

Ra is independently, for each occurrence, H, D, Ci-6 alkyl, C _3-6 cycloalkyl, C _5-10 aromatic, or C _3-6 heterocycloaliphatic;

Rb is independently, for each occurrence, -OH, -CF ³ , -CN, -ORc, -SO ₂ Rc, -NRdRd, -N(H)SO ₂ Rc, -C(O)OH, -N(H) C(O)Rc, -C(O)ORc, -C(O)NRdRd, =O, or halogen;

Rc is independently, for each occurrence, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heteroalicyclyl, aralkyl, C _1-6 alkyl substituted with 1,2 or 3 Re, Cs-aromatic i, C _5-10 aromatic substituted with 1,2 or 3 Re;

Rd is independently, for each occurrence, H, C _1-6 alkyl optionally substituted with 1, 2 or 3 Re, C _3-6 cycloalkyl optionally substituted with 1, 2 or 3 Re, C _3-6 heteroalicyclyl optionally substituted with 1,2 or 3 Re, C _5-10 aromatic optionally substituted with 1,2 or 3 Ra or Rb, or two Rd groups, together with the nitrogen attached to it, form an optionally substituted C _3-6 heteroalicyclyl moiety with C _1-6 alkyl and optionally interrupted with one or two -O- or -N(R ₈ ), where R ₉ is R ₇ 0; and

Re is independently, for each occurrence, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, or -ORa. Paragraph 6. The compound of any one of paragraphs 1 -5, in which ring A is

Paragraph 7. [Omitted].

Paragraph 8. The compound of any one of paragraphs 1-6, wherein R2 is H, 3- to 10-membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy substituted cyclohexyl and/or hydroxy, unsubstituted C _1-6 alkyl, or C _1-6 alkyl substituted with -OH, amino, alkoxy or heterocycloaliphatic.

Paragraph 9. The compound of any one of paragraphs 5-8, wherein R2 is Ra, Ra substituted with Rb, or Ra substituted with 1 or 2 Rc, or Ra substituted with Rd.

Paragraph 10. The compound of any one of paragraphs 1-9, wherein R2 is H, CH ³ ,

Paragraph 11. The compound of paragraph 1, in which:

ring A is pyridinyl or pyrazinyl;

R1 is H; and

R2 is H, 3 to 10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy and/or hydroxy substituted cyclohexyl, unsubstituted C _1-6 alkyl, or C _1- alkyl. ₆ substituted with -OH, amino, alkoxy or heterocycloaliphatic.

Paragraph 12. The compound of paragraph 1, in which:

each Z1, Z2, Z3, and Z4, is independently N or CR3, wherein at least one of Z1, Z2, Z3, and Z4 is N; each R3 is independently H, aliphatic, or heteroaliphatic; and

R4 is halogen, heteroaryl, heterocycloaliphatic, aryl, -NH-heteroaryl, or -O-heteroaryl.

Paragraph 13. The compound of paragraph 12, in which the remainder

is pyridinyl, pyrimidinyl, or pyrazinyl.

Paragraph 14. The compound of paragraph 12 or paragraph 13, where Z1 is N.

Paragraph 15. The compound of any one of paragraphs 12-14, wherein Z1 is N, and Z2, Z3, and Z4 are CR3. Paragraph 16. The compound of any one of paragraphs 12-14, wherein Z1 and Z2 are N, and Z3 and Z4 are CR3. Paragraph 17. The compound of paragraph 12 or paragraph 13, where Z1 and Z3 are N, and Z2 and Z4 are CR3.

Paragraph 18. The compound of paragraph 12 or paragraph 13, where Z ¹ and Z ⁴ are N, and Z ² and Z ³ are CR ³ .

Paragraph 19. The compound of paragraph 12 or paragraph 13, where Z ³ is N, and Z1, Z2, and Z4 are CR ³ .

Paragraph 20. The compound of any one of paragraphs 12-19, wherein R1 is H.

Paragraph 21. [Omitted].

Paragraph 22. The compound of any one of paragraphs 1 to 20, wherein R4 is Br, 5- to 10-membered heteroaryl, 3- to 6-membered heterocycloaliphatic, 6- to 10-membered aryl, -NH-(5-membered heteroaryl to 10 membered), or -O-(5 to 10 membered heteroaryl).

Paragraph 23. The compound of paragraph 22, wherein R4 is pyridinyl, pyrimidinyl, pyrazolyl, -NH-pyrazolyl, pyrrolyl, -O-pyridinyl, -NH-pyridinyl, indolyl, furanyl, -NH-benzopyrazolyl, pyrrolopyridinyl, phenyl, tetrahydropyridinyl, piperidinyl, or 2-oxo-1,2-dihydropyridinyl.

Paragraph 24. The compound of any one of paragraphs 1 or 20, wherein R4 is Br; unsubstituted pyridinyl; C _1-6 alkyl-substituted pyridinyl, haloalkyl, amino, heterocycloaliphatic, cycloalkyl, -CN, alkoxy, -O-heterocycloaliphatic, -NH-heterocycloaliphatic, halogen, sulfonamide, -O-benzyl, carboxyl, sulfonyl, -NH-cycloalkyl , or amide; unsubstituted pyrimidinyl; unsubstituted pyrazolyl; C ¹ -6 alkyl substituted pyrazolyl; -NH-pyrazolyl unsubstituted; -NH-pyrazolyl substituted with C _1-6 alkyl, or heteroaryl; pyrrolyl; -O-pyridinyl unsubstituted; -O-pyridinyl substituted with amino; -NH-pyridinyl substituted with C _1-6 alkyl, haloalkyl, or heterocycloaliphatic; unsubstituted indolyl; alkoxy substituted indolyl; furanyl; -NH-benzopyrazolyl; pyrrolopyridinyl; unsubstituted phenyl; phenyl substituted with halogen, C _1-6 alkyl, alkoxy, -CN, amino, or sulfonamide; unsubstituted tetrahydropyridinyl; tetrahydropyridinyl substituted with tert-butoxycarbonyl; piperidinyl; or 2-oxo-1,2-dihydropyridinyl.

Paragraph 25. The compound of any one of paragraphs 1-24, wherein R4 is Br,

, wherein y is 0, 1, or 2, and each Rp is independently Ra, Rb, Ra substituted with Rb, or Ra substituted with Rc.

Paragraph 26. The compound of Paragraph 25, where each Rp independently is -CH ³ , -OCH ³ , -NH ² , -CF ³ , F, -CN,

Paragraph 27. [Omitted].

Paragraph 28. The compound of any one of paragraphs 1 -27, in the compound has a formula 2,

wherein each of R5, R6, and _R7 independently is H or alkyl.

Paragraph 29. The compound of paragraph 28, wherein each of R5, R6, and _R7 is H.

Paragraph 30. The compound of paragraph 28 or paragraph 29, wherein each of R5, R6, and _R7 is C ¹ -6 alkyl.

Paragraph 31. The compound of any one of paragraphs 28-30, wherein ring A is pyridin-2-yl or pyrazin-2-yl.

Paragraph 32. The compound of any one of paragraphs 1 -31, in the compound has a formula 3

and each of R ₈ , R 9 , R 10 and R 11 independently is H, aliphatic, halogen, heterocycloaliphatic, alkoxy, or -O-heterocycloaliphatic.

Paragraph 33. The compound of paragraph 32, wherein each of R ₈ , R 9 , R 10 and R 11 is independently H, halogen, 3 to 6 membered heterocycloaliphatic, alkoxy, or -O-(3 to 6 membered heterocycloaliphatic) .

Paragraph 34. The compound of Paragraph 32 or Paragraph 33, wherein R ₈ is H or halogen.

Paragraph 35. The compound of any one of paragraphs 32-34, wherein R9 and R11 are H.

Paragraph 36. The compound of any one of paragraphs 32-35, wherein R10 is H, F, morpholino, N-methylpiperidin-1-yl, methoxy, 2-hydroxy-2-methylpropoxy, or -O-oxetanyl.

Paragraph 37. The compound of any one of paragraphs 32-36, wherein each of _R8 , R9, and R11 e Paragraph 38. The compound of any one of paragraphs 32-37, wherein R9 and R11 are H, and R ₈ and F.

Paragraph 39. The compound of any one of paragraphs 32-36, wherein _R8 , R9, R10, and R11 are each H.

Paragraph 40. The compound of any one of paragraphs 32-39, in the compound has a formula 9

Paragraph 41. The compound of paragraph 40, in which:

R1 is H;

R2 is H, 3 to 10 membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, alkoxy and/or hydroxy substituted cyclobutyl, cyclohexyl, alkoxy and/or hydroxy substituted cyclohexyl, unsubstituted C _1-6 alkyl, or C alkyl _1-6 substituted with -OH, amino, alkoxy, or heterocycloaliphatic;

R4 is Br; unsubstituted pyridinyl; C _1-6 alkyl-substituted pyridinyl, haloalkyl, amino, heterocycloaliphatic, cycloalkyl, -CN, alkoxy, -O-heterocycloaliphatic, -NH-heterocycloaliphatic, halogen, sulfonamide, -O-benzyl, carboxyl, sulfonyl, -NH-cycloalkyl , or amide; unsubstituted pyrimidinyl; unsubstituted pyrazolyl; pyrazolyl substituted with C _1-6 alkyl; -NH-pyrazolyl unsubstituted; -NH-pyrazolyl substituted with C _1-6 alkyl, or heteroaryl; pyrrolyl; -O-pyridinyl unsubstituted; -O-pyridinyl substituted with amino; -NH-pyridinyl substituted with C _1-6 alkyl, haloalkyl, or heterocycloaliphatic; unsubstituted indolyl; alkoxy substituted indolyl; furanyl;

-NH-benzopyrazolyl; pyrrolopyridinyl; unsubstituted phenyl; phenyl substituted with halogen, C _1-6 alkyl, alkoxy,

-CN, amino, or sulfonamide; unsubstituted tetrahydropyridinyl; tetrahydropyridinyl substituted with tert-butoxycarbonyl; piperidinyl; or 2-oxo-1,2-dihydropyridinyl;

R8 is H or F;

R9 and R11 are H; and

R10 is H, F, morpholino, N-methylpiperidinyl, methoxy, 2-hydroxy-2-methylpropoxy, or -O-oxetanyl.

Paragraph 42. The compound of paragraph 41, wherein each of _R8 , R9, R10, and R11 is H.

Paragraph 43. The compound of paragraph 41, wherein R ₈ , R 9 , and R 11 are H, and R 10 is 3- to 6-membered morpholino or N-methylpiperidinyl, methoxy, 2-hydroxy-2-methylpropoxy, or -O- oxetanil.

Paragraph 44. The compound of paragraph 41, wherein _R8 and R10 are F, and R9 and R11 are H.

Paragraph 45. A compound selected from the exemplary compounds described herein.

Paragraph 46. A composition, comprising a compound of any one of paragraphs 1-45, and a pharmaceutically acceptable excipient.

Paragraph 47. The composition of paragraph 46, further comprising an additional therapeutic agent.

Paragraph 48. A method comprising administering to a subject in need thereof an effective amount of a compound of any one of paragraphs 1-45, or a composition of any one of paragraphs 46-47.

Paragraph 49. The method in paragraph 48, for the treatment of a disease or condition for which an IRAK inhibitor is indicated.

Paragraph 50. The method of paragraph 49, wherein the disease is an autoimmune disease, inflammatory disorder, cardiovascular disease, neurodegenerative disorder, allergic disorder, multi-organ failure, renal disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency , graft rejection, lung injury, respiratory disease, ischemic condition, bacterial infection, viral infection, immune regulatory disorder, or a combination thereof.

Paragraph 51. The method of paragraph 49, wherein the disease is amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease , ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, pancreatitis, Kaposi's sarcoma, myelodysplastic syndrome, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, or asthma.

Paragraph 52. The method of paragraph 50, wherein the immune regulatory disorder is rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis , post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, Behcet's disease-associated uveitis, keratitis, keratitis herpes, cornea conica, epithelial dystrophy of the cornea, corneal leukoma, ocular pemphigus, ulcer of Mooren's, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma , late-onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis , mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, der matomyositis , leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposis, eosinophilic fasciitis, lesions of gums, periodontium, alveolar bone, dental bone substance, glomerulonephritis, male pattern alopecia or senile alopecia by preventing hair removal or facilitating hair germination and/or promoting hair generation and growth, muscular dystrophy, pyoderma and syndrome of sezary disease Addison's disease, ischemia-reperfusion injury of organs that occurs after preservation, transplantation or ischemic disease, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure, pulmonary oxygen toxinosis or drugs, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, age-related macular degeneration, vitreous scarring, alkaline burn of the cornea, dermatitis erythema multiforme, linear IgA bullous dermatitis and cementum dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, carcinoma metastasis and hypobaropathy, disease caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, toxin necrosis, viral hepatitis, shock or anoxia, hepatitis B virus, non- N non-B hepatitis, cirrhosis, alcoholic cirrhosis, liver failure, fulminant liver failure, late-onset liver failure, “acute on chronic” liver failure, increased of the chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma, or chronic bacterial infection.

Paragraph 53. A method of inhibiting an IRAK protein, comprising contacting the IRAK protein with an effective amount of a compound of any one of paragraphs 1-45, or a composition of any one of paragraphs 46-47.

Paragraph 54. The method of Paragraph 53, wherein the compound has an EC ⁵⁰ of greater than 0 to 5 µM.

Paragraph 55. The method of Paragraph 53, wherein the compound has an EC ⁵⁰ of greater than 0 to 1 µM.

Paragraph 56. The method of any one of paragraphs 53-55, wherein the IRAK protein is in a subject.

Paragraph 57. The method of any one of paragraphs 53-55, wherein contacting with IRAK protein comprises contacting with IRAK protein in vitro.

Claims (18)

1.A compound, which has a formula 1

or a salt thereof, wherein: ring A is heteroaryl; R1 is H or C _1-6 alkyl; R2 is H, aliphatic, heteroaliphatic, or heterocyclyl; each Z1, Z2, Z3, and Z4, is independently N or CR3, wherein at least one of Z1, ZZ, Z3, and Z4 is N; each R3 is independently H, aliphatic, or heteroaliphatic; and R4 is halogen, heteroaryl, heterocycloaliphatic, aryl, -NH-heteroaryl, or -O-heteroaryl. The compound of claim 1, wherein ring A is

3. The compound of claim 1 or claim 2, wherein R2 is H, 3- to 10-membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, alkoxy- and/or hydroxy-substituted cyclobutyl, cyclohexyl, alkoxy-substituted cyclohexyl, and/or or hydroxy, unsubstituted C _1-6 alkyl, or C _1-6 alkyl substituted with -OH, amino, alkoxy, or heterocycloaliphatic. 4. The compound of any one of claims 1-3, wherein R2 is H, CH ³ ,

The compound of any one of claims 1-4, wherein the moiety is pyrimidinyl or pyrazinyl.

it's pyridinyl, 6. The compound of claim 5, wherein Z1 is n The compound of claim 5, wherein Z1 is N, and Z2, Z3, and Z4 are CR3; Z1 and Z2 are N, and Z3 and Z4 are CR3; Z1 and Z3 are N, and Z2 and Z4 are CR3; Z1 and Z4 are N, and Z2 and Z3 are CR3; either Z3 is N, and Z1, Z2, and Z4 are CR3. 8. The compound of any one of claims 1-7, wherein R1 is H. 9. The compound of any one of claims 1-8, wherein R4 is Br, 5 to 10 membered heteroaryl, 3 to 6 membered heterocycloaliphatic, 6 to 10 membered aryl, -NH-(5 to 6 membered heteroaryl 10 membered), or -O-(5 to 10 membered heteroaryl). 10. The compound of claim 9, wherein R4 is pyridinyl, pyrimidinyl, pyrazolyl, -NH-pyrazolyl, pyrrolyl, -O-pyridinyl, -NH-pyridinyl, indolyl, furanyl, -NH-benzopyrazolyl, pyrrolopyridinyl, phenyl, tetrahydropyridinyl, piperidinyl, or 2-oxo-1,2-dihydropyridinyl. 11. The compound of claim 9, wherein R4 is Br; unsubstituted pyridinyl; C _1-6 alkyl-substituted pyridinyl, haloalkyl, amino, heterocycloaliphatic, cycloalkyl, -CN, alkoxy, -O-heterocycloaliphatic, -NH-heterocycloaliphatic, halogen, sulfonamide, -O-benzyl, carboxyl, sulfonyl, -NH-cycloalkyl , or amide; unsubstituted pyrimidinyl; unsubstituted pyrazolyl; pyrazolyl substituted with C _1-6 alkyl; -NH-pyrazolyl unsubstituted; -NH-pyrazolyl substituted with C _1-6 alkyl, or heteroaryl; pyrrolyl; -O-pyridinyl unsubstituted; -O-pyridinyl substituted with amino; -NH-pyridinyl substituted with C _1-6 alkyl, haloalkyl, or heterocycloaliphatic; unsubstituted indolyl; alkoxy substituted indolyl; furanyl; -NH-benzopyrazolyl; pyrrolopyridinyl; unsubstituted phenyl; phenyl substituted with halogen, C _1-6 alkyl, alkoxy, -CN, amino, or sulfonamide; unsubstituted tetrahydropyridinyl; tetrahydropyridinyl substituted with tert-butoxycarbonyl; piperidinyl; or 2-oxo-1,2-dihydropyridinyl. The compound of any one of claims 10-11, wherein: R4 is Br,

y is 0, 1 or 2; and each Rp is independently -CH3, -OCH ₃ , -NH2, -CF3, F, -CN,

The compound of claim 1, selected from: I-1: 6-bromo-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide; I-2: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-3: 5'-fluoro-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-4: 5'-cyano-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-5: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(pyrimidin-5-yl)picolinamide; I-6: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-5-yl)picolinamide; I-7: 6-(3-methyl-1H-pyrazol-5-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide; I-8: 6-(1-methyl-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide; 1-9: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide; I-10: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(1 H-pyrazol-2-yl)picolinamide; I-11: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)picolinamide; I-12: 5'-methyl-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-13: 5'-cyclopropyl-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-14: 5'-(2-hydroxypropan-2-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'- bipyridine]-6-carboxamide; I-15: 2'-methyl-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide; I-16: 6'-methyl-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-17: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(trifluoromethyl)-[2,3'-bipyridine]-6-carboxamide ; I-18: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-(trifluoromethyl)-[2,4'-bipyridine]-6-carboxamide ; I-19: 5'-methoxy-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-20: 6'-methoxy-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-21: 2'-methoxy-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide; 1-22: 5'-isopropoxy-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-23: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-((tetrahydro-2H-pyran-4-yl)oxy)-[ 2,3'-bipyridine]-6-carboxamide; I-24: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(2,2,2-trifluoroethoxy)-[2,3'- bipyridine]-6-carboxamide; I-25: 5'-amino-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-26: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(methylamino)-[2,3'-bipyridine]-6-carboxamide ; I-27: 5'-(cyclopropylamino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide ; I-28: 5'-(isopropylamino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide ; I-29: 5'-(tert-butylamino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]-6 -carboxamide; I-30: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-((tetrahydro-2H-pyran-4-yl)amino)-[ 2,3'-bipyridine]-6-carboxamide; I-31: 5'-((2-methoxyethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin ]-6-carboxamide; I-32: 5'-((cyclopropylmethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide; I-33: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-((2,2,2trifluoroethyl)amino)-[2,3' - bipyridine]-6-carboxamide; I-34: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(methylsulfonamido)-[2,3'-bipyridine]-6-carboxamide ; I-35: 5'-(dimethylamino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide ; I-36: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(pyrrolidin-1-yl)-[2,3'-bipyridin] -6-carboxamide; I-37: N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-5'-morpholino-[2,3'-bipyridine]-6-carboxamide; I-38: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(4-methylpiperazin-1-yl)-[2,3'- bipyridine]-6-carboxamide; I-39: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(methylsulfonyl)-[2,3'-bipyridine]-6-carboxamide ; I-40: N6-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-5',6-dicarboxamide; I-41: N6-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-2',6-dicarboxamide; I-42: 2'-cyano-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide; I-43: 6'-amino-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-44: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl )picolinamide; I-45: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrrolo[3,2-b]pyridin-6-yl )picolinamide; I-46: 6-(1H-indol-5-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide; I-47: 6-(1H-indol-6-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide; I-48: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-phenylpicolinamide; I-49: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(m-tolyl)picolinamide; I-50: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(p-tolyl)picolinamide; I-51: 6-(3-methoxyphenyl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide; I-52: 6-(4-methoxyphenyl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide; I-53: 6-(3-cyanophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide; I-54: 6-(4-cyanophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide; I-55: 6-(3-fluorophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide; I-56: 6-(4-fluorophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide; I-57: 6-(3-aminophenyl)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide; I-58: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(3-(methylamino)phenyl)picolinamide; I-59: 6-(3-(dimethylamino)phenyl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide; I-60: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(3-(methylsulfonamido)phenyl)picolinamide; I-61 -((1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)carbamoyl)-3',6'-dihydro-[2,4'-bipyridin]-1 tert-Butyl '(2'H)-carboxylate; I-62: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-1',2',3',6'-tetrahydro-[2,4' -bipyridine]-6-carboxamide; I-63: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(piperidin-4-yl)picolinamide; I-64-((1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)carbamoyl)-5',6'-dihydro-[2,3'-bipyridin]-1 tert-Butyl '(2'H)-carboxylate; I-65: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-1',2',5',6'-tetrahydro-[2,3' -bipyridine]-6-carboxamide; I-66: 6-bromo-N-(3-(5-methoxypyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)picolinamide; I-67: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-5-yl)picolinamide; I-68: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide; I-69: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridine]-6-carboxamide ; I-70: 5'-isopropoxy-N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide ; I-71: 5'-(isopropylamino)-N-(3-(5-methoxypyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)-[2,3'-bipyridin]-6 -carboxamide; I-78: 6-(3-methyl-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide; I-79: 6-bromo-N-(1-isopropyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide; I-80: N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide; I-81: N-(1-isopropyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridine]-6-carboxamide; I-82: 6-bromo-N-(1 -(2-morpholinoethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide; I-83: N-(1 -(2-morpholinoethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide; I-84: 5'-methyl-N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]-6 -carboxamide; I-85: 6-bromo-N-(1 -(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide; I-86: N-(1 -(2-(4-methylpiperazin-1 -yl)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H- pyrazol-4-yl)picolinamide; I-87: 5'-methyl-N-(1 -(2-(4-methylpiperazin-1 -yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[ 2,3'-bipyridine]-6-carboxamide; I-88: N-(1 -(2-hydroxyethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide; I-89: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(pyridin-4-yloxy)picolinamide ; I-90: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridin]-6 -carboxamide; I-91: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-oxo-1',2'-dihydro-[2,4'- bipyridine]-6-carboxamide; I-92: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6'-oxo-1',6'-dihydro-[2,3'- bipyridine]-6-carboxamide; I-93: N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-5'-(2,2,2-trifluoroethoxy)-[2,3'- bipyridine]-6-carboxamide; I-94: N-(3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide; I-95: N-(1 -(2-methoxyethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide; I-96: 2'-methoxy-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4' -bipyridine]-6-carboxamide; I-97: 6'-amino-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3' -bipyridine]-6-carboxamide; I-98: 6'-acetamido-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3' -bipyridine]-6-carboxamide; I-99: 2'-methoxy-N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide; I-100: N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide; I-101: N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-102: 6'-acetamido-N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-103: 2'-(benzyloxy)-N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide ; I-104: N-(1 -(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide ; I-105: N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-5'-(2,2,2-trifluoroethoxy)-[2,3 formate '-bipyridine]-6-carboxamide; I-106: N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide formate; I-107: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide formate; I-108: N-(1-(2-hydroxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide formate; I-109: 5-(1 -(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)nicotinamide ; I-110: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[3,4'-bipyridine]-5-carboxamide; I-111: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[3,3'-bipyridine]-5-carboxamide; I-112: N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; I-113: 6-bromo-N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)picolinamide; I-114: 5'-methyl-N-(-(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide; I-115: 5'-(methylsulfonamido)-N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'- bipyridine]-6-carboxamide; I-116: N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide ; I-117: N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-3-yl)picolinamide ; I-118: N-(1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-4-((1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)amino)pyrimidine-2-carboxamide; I-119: (methylsulfonyl)(6-((1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)carbamoyl)-[2,3'- sodium bipyridin]-5'-yl)amide; I-120: N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-4-(5-methylpyridin-3-yl)pyrimidine-2-carboxamide; I-121: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(5-methylpyridin-3-yl)pyrazine-2-carboxamide; I-122: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)pyrazine-2-carboxamide; I-123: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl)pyrazine-2-carboxamide; I-124: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrimidine-2-carboxamide; I-125: N-(1 -(1,3-dihydroxypropan-2-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide; I-126: N-(1 -( ¹ ,3-dihydroxypropan-2-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3 '-bipyridine]-6-carboxamide; I-127: N-(1 -( ¹ ,3-dihydroxypropan-2-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4 -yl)picolinamide; I-128: 4-((1 H-pyrazol-3-yl)amino)-N-(1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)pyrimidin-2- carboxamide; I-129: 4-((3-methyl-1H-pyrazol-4-yl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl) pyrimidine-2-carboxamide; I-130: 5'-isopropoxy-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridin] -6-carboxamide; -131: 5'-fluoro-N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]- 6-carboxamide; -132: N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-(trifluoromethyl)-[2,3'-bipyridine ]-6-carboxamide; -133: N6-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridin]-5',6- dicarboxamide; -134: 6-(1 -methyl-1 H-pyrazol-4-yl)-N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4- il)picolinamide; -135: 6-((1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)carbamoyl)-[2,3'-bipyridin]-5 acid '-carboxylic; -136: 6-(3-methyl-1 H-pyrazol-5-yl)-N-(1 -(oxetan-3-yl)-3-(pyridin-2-yl)-1 H-pyrazol-4- il)picolinamide; -137: N-(1-methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-2-(1 H-pyrazol-4-yl)pyrimidine-4-carboxamide; -138: N-(1 -methyl-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)-2-(1 H-pyrazol-3-yl)pyrimidine-4-carboxamide; -139: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(pyridin-4-yloxy) formate picolinamide; -140: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridin]- formate 6-carboxamide; -141: 2'-methoxy-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4 formate '-bipyridine]-6-carboxamide; -142: 6'-amino-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3 formate '-bipyridine]-6-carboxamide; -143: 6'-acetamido-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3 formate '-bipyridine]-6-carboxamide; -144: 3'-fluoro-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4 formate '-bipyridine]-6-carboxamide; -145: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-3'-methyl-[2,4 formate '-bipyridine]-6-carboxamide; -146: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-methyl-[2,4 formate '-bipyridine]-6-carboxamide; -147: 6-(6-methoxy-1H-indol-2-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H formate -pyrazol-4-yl)picolinamide; -148: 6-(1 -(3-chlorophenyl)-1H-pyrazol-4-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl) formate )-1 H-pyrazol-4-yl)picolinamide; -149: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3 formate '-bipyridine]-6-carboxamide; -150: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-3-3) formate -yl)picolinamide; -151: 6-(furan-3-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazole 2,2,2-trifluoroacetate -4-yl)picolinamide; -152: 6-(furan-2-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H- 2,2,2-trifluoroacetate pyrazol-4-yl)picolinamide; -153: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-formate -yl)picolinamide; -154: 6-((1 H-indazol-5-yl)amino)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H- formate pyrazol-4-yl)picolinamide; -155: 6-((2H-indazol-5-yl)amino)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazole formate -4-yl)picolinamide; -156: 6-((2-aminopyridin-4-yl)oxy)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazole formate -4-yl)picolinamide; -157: 6-((2,5-dimethylpyridin-4-yl)amino)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H formate -pyrazol-4-yl)picolinamide; -158: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-((6-(4- methylpiperazin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)picolinamide; -159: 2'-((cyclopropylmethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-[2,4'-bipyridin] formate -6-carboxamide; -160: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide 2,2,2-trifluoroacetate ; -161: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-((2,2,2-trifluoroethyl)amino)-[2 formate ,4'-bipyridine]-6-carboxamide; -162: N-(1 -(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridin]- formate 6-carboxamide; -163: N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide formate; -164: 5'-methyl-N-(3-(pyridin-2-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-4-yl)-[2,3' -bipyridine]-6-carboxamide; -165: 6-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- il)picolinamide; -166: 6-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- il)picolinamide; -167: N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridin]-6 -carboxamide; -168: N-(1 -(2-methoxyethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridin]-6- carboxamide; -169: N-(1 -(3-methoxypropyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridin]-6- carboxamide; -170: 5'-methyl-N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide; -171: N-(1 -methyl-3-(5-morpholinopyridin-2-yl)-1 H -pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide; -172: N-(1 -methyl-3-(5-morpholinopyridin-2-yl)-1 H -pyrazol-4-yl)-6-(1 H-pyrazol-3-yl)picolinamide; -173: 5'-methyl-N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-[2,3 '-bipyridine]-6-carboxamide; -174: N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4 -yl)picolinamide; -175: N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3 -yl)picolinamide; -176: 5'-methyl-N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1H-pyrazol-4-yl)-[2,3'-bipyridin]-6- dihydrochloride carboxamide; -177: 5'-methyl-N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-[2 dihydrochloride ,3'-bipyridine]-6-carboxamide; -178: N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1 H-pyrazol-4-yl)-5'-methyl-[2,3 '-bipyridine]-6-carboxamide; -179: N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-(1H-pyrazol-4 -yl)picolinamide; -180: N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-(1H-pyrazol-3 -yl)picolinamide; -181: 5'-methyl-N-(1-methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,3'- bipyridine]-6-carboxamide; -182: N-(1 -methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl )picolinamide; -183: N-(1-methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl )picolinamide; -184: N-(3-(3,5-difluoropyridin-2-yl)-1 -((1 r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-6-(1H -pyrazol-4-yl)picolinamide; -185: 3'-fluoro-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'- bipyridine]-6-carboxamide; -186: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-3'-methyl-[2,4'- bipyridine]-6-carboxamide; -187: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-methyl-[2,4'- bipyridine]-6-carboxamide; -188: 6-(6-methoxy-1 H-indol-2-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazole -4-yl)picolinamide; -189: 6-(1 -(3-chlorophenyl)-1 H-pyrazol-4-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)- 1 H-pyrazol-4-yl)picolinamide; -190: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'- bipyridine]-6-carboxamide; -191: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-3-yl )picolinamide; -192: 6-(furan-3-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H -pyrazol-4-yl)picolinamide; I-193: 6-(furan-2-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide ; I-193: 6-(furan-2-yl)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)picolinamide ; I-194: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol-4- il)picolinamide; I-195: 6-((1 H-indazol-5-yl)amino)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazole -4-yl)picolinamide; I-196: 6-((2H-indazol-5-yl)amino)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol- 4-yl)picolinamide; I-197: 6-((2-aminopyridin-4-yl)oxy)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol- 4-yl)picolinamide; I-198: 6-((2,5-dimethylpyridin-4-yl)amino)-N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H- pyrazol-4-yl)picolinamide; I-199: N-(1 -(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-6-((6-(4-methylpiperazine -1-yl)-5-(trifluoromethyl)pyridin-3-yl)amino)picolinamide; I-200: 2'-((cyclopropylmethyl)amino)-N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridin]- 6-carboxamide; I-201: N-(1-methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-[2,4'-bipyridine]-6-carboxamide; I-202: N-(1 -methyl-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-2'-((2,2,2 trifluoroethyl)amino)-[2,4 '-bipyridine]-6-carboxamide; I-203: N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1 H-pyrazol-4-yl)-5'-methyl-[2,3'-bipyridin]-6 -carboxamide; I-204: N-(1 -(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-6-(1H-pyrazol-4-yl)picolinamide; I-205: N-(1 -((1 r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-6-(1 H-pyrazol- 4-yl)picolinamide; I-206: N-(1 ^-((1r ,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-5'-methyl-[2, 3'-bipyridine]-6-carboxamide; I-207: N-(1 -methyl-3-(pyrazin-2-yl)-1 H -pyrazol-4-yl)-6-(1 H-pyrazol-4-yl)picolinamide; either I-208: 5'-methyl-N-(1-methyl-3-(pyrazin-2-yl)-1 H-pyrazol-4-yl)-[2,3'-bipyridine]-6-carboxamide. 14. A composition comprising a compound of any one of claims 1-13 and a pharmaceutically acceptable excipient. A compound according to any one of claims 1-13, or a composition of claim 14, for use in a method of treating a disease or condition. A compound according to any one of claims 1-13, or a composition of claim 14, for use in a method of inhibiting an IRAK protein, the method comprising contacting the IRAK protein with an effective amount of the compound or the composition. The compound or composition for use according to claim 15, wherein the disease or condition is a disease or condition for which an IRAK inhibitor is indicated. The compound or composition for use according to claim 17, wherein the disease or condition is an autoimmune disease, inflammatory disorder, cardiovascular disease, neurodegenerative disorder, allergic disorder, multiple organ failure, renal disease, platelet aggregation, cancer, transplantation, sperm motility, red blood cell deficiency, graft rejection, lung injury, respiratory disease, ischemic condition, bacterial infection, viral infection, immune regulation disorder, or a combination thereof.